TW202045497A

TW202045497A - A method for treating fatty liver diseases and/or fatty liver hepatitis

Info

Publication number: TW202045497A
Application number: TW109106569A
Authority: TW
Inventors: 姜媛媛; 仲偉婷; 趙焰平; 王紅軍; 趙靜; 李晶; 劉偉娜; 周麗瑩; 劉亞男
Original assignee: 大陸商北京泰德製藥股份有限公司
Priority date: 2019-03-01
Filing date: 2020-02-27
Publication date: 2020-12-16
Also published as: EP3932404A4; CA3132228A1; CN113490493A; AU2020230574A1; EP3932404A1; IL285989A; WO2020177587A1; JP2022522486A; US20220378743A1; KR20210137086A

Abstract

The present invention falls within the field of biological medicine, and specifically relates to a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis. The method compirses administering, to an individual in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, an ester, a stereoisomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug thereof.

Description

Method for treating fatty liver disease and/or steatohepatitis

本發明屬於生物醫藥領域，並具體涉及預防、緩解及/或治療脂肪性肝病及/或脂肪性肝炎的方法，其包括向需要其的個體給藥有效量的式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥。The present invention belongs to the field of biomedicine, and specifically relates to a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis, which comprises administering an effective amount of a compound of formula (I) or its pharmacy to an individual in need thereof The above acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs.

脂肪性肝病是指脂肪沉積在肝細胞中而引發肝病的一類疾病的總稱，其包括酒精性脂肪性肝病及非酒精性脂肪性肝病(NAFLD)。Fatty liver disease is a general term for a class of diseases in which fat is deposited in liver cells and causes liver disease, including alcoholic fatty liver disease and non-alcoholic fatty liver disease (NAFLD).

酒精性脂肪性肝病是由於長期大量飲酒導致的肝臟疾病，臨床症狀為非特異性的，其可無症狀，或有右上腹脹痛、食欲不振、乏力、體重減輕等。Alcoholic fatty liver disease is a liver disease caused by long-term heavy drinking. The clinical symptoms are non-specific. It may be asymptomatic, or have right upper abdominal distension and pain, loss of appetite, fatigue, weight loss, etc.

非酒精性脂肪性肝病及非酒精性脂肪性肝炎(NASH)是常見的肝病。在組織病理學上，這些病症類似於酒精性肝病，但是它們出現在很少飲酒或不飲酒的人中。肝臟中的病理學變化包括但不限於肝細胞中脂肪積累、肝細胞變性跡象、炎性細胞浸潤、肝細胞結節形成、肝硬化及肝細胞癌。迄今，不存在針對這些病症的特異性療法。因此，對提供治療這些病症的方法存在需求。Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common liver diseases. Histopathologically, these conditions are similar to alcoholic liver disease, but they appear in people who rarely or do not drink alcohol. Pathological changes in the liver include, but are not limited to, fat accumulation in hepatocytes, signs of hepatocyte degeneration, inflammatory cell infiltration, hepatocyte nodule formation, liver cirrhosis, and hepatocellular carcinoma. To date, there is no specific therapy for these conditions. Therefore, there is a need to provide methods for treating these conditions.

在一個方面中，本發明提供預防、緩解及/或治療脂肪性肝病及/或脂肪性肝炎的方法，其包括向需要其的個體給藥有效量的式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥：

式(I) 其中： X及Y各自獨立地選自直接鍵、C(=O)、O、S(=O)_i 及NR； R選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、飽和或部分不飽和的C_3-10 環烴基、飽和或部分不飽和的3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基，該環烴基及雜環基中至多2個環成員為C(=O)；環A及環B各自獨立地選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環和5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)，條件是當環B為含有氮原子的雜環時，環B不通過該氮原子與X連接；環C選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)；環D不存在或者選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)；環E選自

、

及

；環F選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)； R¹ 選自H、-NH₂ 、C_1-6 烷基、C_6-10 芳基、5-14員雜芳基、N-甲基四氫吡咯基、N-甲基哌啶基、

、乙醯基、

、

、

、-C(=O)-(C_1-6 亞烷基)_n -CF₃ 、-C(=O)-(C_1-6 亞烷基)_n -CN、-C(=O)-(飽和或部分不飽和的C_3-10 環烴基)、-NHC(=O)-(飽和或部分不飽和的C_3-10 環烴基)、-C(=O)-(飽和或部分不飽和的3-10員雜環基)、-C(=O)-C_1-6 亞烷基-(飽和或部分不飽和的3-10員雜環基)、-C(=O)-(5-14員雜芳基)、-C(=O)-C_1-6 亞烷基-NH(C_1-6 烷基)、-C(=O)-C_1-6 亞烷基-N(C_1-6 烷基)₂ 、N-甲基哌嗪取代的乙醯基、-S(=O)₂ R^1a 、-P(=O)R^1a R^1b 、

、

、

、

、

、

、

及

；條件是，當R¹ 及R¹⁰ 中一個為C_1-6 烷基且另一個為H或C_3-10 環烴基時，X及Y中至少一個為直接鍵且環C不是5員雜芳環；當R¹ 及R¹⁰ 中一個為H且另一個為

時，環C不是5員雜芳環；當R¹ 及R¹⁰ 均為H時，環A包含至少1個氮原子且不為5或6員環；當R¹ 及R¹⁰ 中一個為H且另一個為

時，環C不是5員雜芳環；並且當R¹ 及R¹⁰ 中一個為H且另一個為H或乙醯基時，環D不存在； R^1a 及R^1b 各自獨立地選自H、鹵素、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-C(=O)R⁵ 、-OC(=O)R⁵ 、-C(=O)OR⁵ 、-OR⁵ 、-SR⁵ 、-S(=O)R⁵ 、-S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、-NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、-NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、-C_1-6 亞烷基-NR⁵ R⁶ 、-C_1-6 亞烷基-OR⁵ 及-O-C_1-6 亞烷基-NR⁵ R⁶ ，條件是當R^1a 及R^1b 之一為正丙基時，另一個不為H；或者R^1a 及R^1b 連同其所連接的原子共同構成3-12員雜環或雜芳環； R² 、R³ 、R⁴ 、R⁷ 、R⁸ 、R⁹ 及R¹⁰ 在每次出現時各自獨立地選自H、鹵素、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-C(=O)R⁵ 、-OC(=O)R⁵ 、-C(=O)OR⁵ 、-OR⁵ 、-SR⁵ 、-S(=O)R⁵ 、-S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、-NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、-NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、-C_1-6 亞烷基-NR⁵ R⁶ 、-C_1-6 亞烷基-O(P=O)(OH)₂ 及-O-C_1-6 亞烷基-NR⁵ R⁶ ；上述烷基、亞烷基、烯基、炔基、環烴基、烴環、雜環基、雜環、芳基、芳環、雜芳基、雜芳環及芳烷基在每次出現時各自視情況經一個或多個獨立地選自下列的取代基取代：鹵素、羥基、氧代、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、=N-OR⁵ 、-C(=NH)NH₂ 、-C(=O)R⁵ 、-OC(=O)R⁵ 、-C(=O)OR⁵ 、-OR⁵ 、-SR⁵ 、-S(=O)R⁵ 、-S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、-NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、-NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、-C_1-6 亞烷基-NR⁵ R⁶ 及-O-C_1-6 亞烷基-NR⁵ R⁶ ，該烷基、環烴基、雜環基、芳基、雜芳基及芳烷基進一步視情況經一個或多個獨立地選自下列的取代基取代：鹵素、羥基、氧代、胺基、氰基、硝基、C_1-6 烷基、C_3-6 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基； R⁵ 及R⁶ 在每次出現時各自獨立地選自H、C_1-6 烷基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基； m在每次出現時各自獨立地為0、1、2或3的整數； n為0、1或2的整數； i為0、1或2的整數；並且 g為0、1、2、3或4的整數；其中該脂肪性肝病較佳為酒精性脂肪性肝病(AFLD)或非酒精性脂肪性肝病(NAFLD)，該脂肪性肝炎較佳為酒精性脂肪性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)。In one aspect, the present invention provides a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) or its pharmaceutically acceptable Accepted salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:

Formula (I) wherein: X and Y are each independently selected from direct bond, C(=O), O, S(=O) _i and NR; R is selected from H, C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl Group and C _6-12 aralkyl group, in the cyclic hydrocarbon group and heterocyclic group, at most two ring members are C(=O); ring A and ring B are each independently selected from saturated or partially unsaturated C _3-10 Hydrocarbon ring, saturated or partially unsaturated 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring. Up to 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O), The condition is that when ring B is a heterocyclic ring containing a nitrogen atom, ring B is not connected to X through the nitrogen atom; ring C is selected from a saturated or partially unsaturated C _3-10 hydrocarbon ring, a saturated or partially unsaturated 3- 10-membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); ring D does not exist or is selected from saturated or partially non-existent Saturated C _3-10 hydrocarbon ring, saturated or partially unsaturated 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring. Up to 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); ring E is selected from

,

and

; Ring F is selected from saturated or partially unsaturated C _3-10 hydrocarbon ring, saturated or partially unsaturated 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring, the hydrocarbon ring and At most two ring members in the heterocyclic ring are C(=O); R ^{1 is} selected from H, -NH ₂ , C _1-6 alkyl, C _6-10 aryl, 5-14 membered heteroaryl, N-methyl Tetrahydropyrrolyl, N-methylpiperidinyl,

, Acetyl,

,

, -C(=O)-(C _1-6 alkylene) _n -CF ₃ , -C(=O)-(C _1-6 alkylene) _n -CN, -C(=O)-( Saturated or partially unsaturated C _3-10 cyclic hydrocarbon group), -NHC(=O)-(saturated or partially unsaturated C _3-10 cyclic hydrocarbon group), -C(=O)-(saturated or partially unsaturated 3-10 membered heterocyclic group), -C(=O)-C _1-6 alkylene-(saturated or partially unsaturated 3-10 membered heterocyclic group), -C(=O)-(5- 14-membered heteroaryl), -C(=O)-C _1-6 alkylene-NH(C _1-6 alkyl), -C(=O)-C _1-6 alkylene-N(C _1-6 alkyl) ₂ , N-methylpiperazine substituted acetyl group, -S(=O) ₂ R ^1a , -P(=O)R ^1a R ^1b ,

,

and

; The condition is that when one of R ¹ and R ¹⁰ is C _1-6 alkyl and the other is H or C _3-10 cycloalkyl, at least one of X and Y is a direct bond and ring C is not a 5-membered heteroaromatic Ring; when one of R ¹ and R ¹⁰ is H and the other is

When R ¹ and R ¹⁰ are both H, ring A contains at least one nitrogen atom and is not a 5- or 6-membered ring; when one of R ¹ and R ¹⁰ is H and The other is

When, ring C is not a 5-membered heteroaromatic ring; and when one of R ¹ and R ¹⁰ is H and the other is H or acetyl, ring D does not exist; R ^1a and R ^1b are each independently selected from H, Halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _{6- 10} aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O) -NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-OR ⁵ and -OC _1-6 alkylene-NR ⁵ R ⁶ , provided that R ^When one of ^1a and R ^1b is n-propyl, the other is not H; or R ^1a and R ^1b together with the atoms to which they are connected form a 3-12 member heterocyclic or heteroaromatic ring; R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from H, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O )R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ ,- S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 Alkylene-O(P=O)(OH) ₂ and -OC _1-6 Alkylene-NR ⁵ R ⁶ ; The above-mentioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, hetero Cyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic and aralkyl groups are each substituted with one or more substituents independently selected from the following when each occurrence: halogen, hydroxy, Oxo, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O)R ⁵ , -OC( =O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S (=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 alkylene-NR ⁵ R ^6. The alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group are further optionally substituted with one or more substituents independently selected from the following: halogen, hydroxyl, oxo, amine , Cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, and C _6-12 aralkyl R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-10 cyclic hydrocarbon group, 3-10 membered heterocyclic group, C _6-10 aryl, 5- 14-membered heteroaryl and C _6-12 aralkyl; m is each independently an integer of 0, 1, 2 or 3 at each occurrence; n is an integer of 0, 1, or 2; i is 0, 1, or 2; and g is an integer of 0, 1, 2, 3, or 4; wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), the fatty liver disease Preferably, it is alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).

在另一方面中，本發明提供上述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥在製備用於預防、緩解及/或治療脂肪性肝病及/或脂肪性肝炎的藥物中的用途，其中該脂肪性肝病較佳為酒精性脂肪性肝病(AFLD)或非酒精性脂肪性肝病(NAFLD)，該脂肪性肝炎較佳為酒精性脂肪性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)。In another aspect, the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound The use of metabolites or prodrugs in the preparation of drugs for the prevention, alleviation and/or treatment of fatty liver disease and/or steatohepatitis, wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non Alcoholic fatty liver disease (NAFLD), the steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).

在另一方面中，本發明提供上述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥，其用於預防、緩解及/或治療脂肪性肝病及/或脂肪性肝炎，其中該脂肪性肝病較佳為酒精性脂肪性肝病(AFLD)或非酒精性脂肪性肝病(NAFLD)，該脂肪性肝炎較佳為酒精性脂肪性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)。In another aspect, the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound , Metabolites or prodrugs, which are used to prevent, alleviate and/or treat fatty liver disease and/or steatohepatitis, wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), the steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).

定義除非在下文中另有定義，本文中所用的所有技術術語及科學術語的含義意圖與本發明所屬技術領域中具有通常知識者通常所理解的相同。提及本文中使用的技術意圖指在本發明所屬技術領域中通常所理解的技術，包括那些對本發明所屬技術領域中具有通常知識者顯而易見的技術的變化或等效技術的替換。雖然相信以下術語對於本發明所屬技術領域中具有通常知識者很好理解，但仍然闡述以下定義以更好地解釋本發明。 Definitions Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those with ordinary knowledge in the technical field to which the present invention belongs. Mention of the technology used herein is intended to refer to the technology generally understood in the technical field of the present invention, including those technical changes or equivalent technical substitutions that are obvious to a person with ordinary knowledge in the technical field of the present invention. Although it is believed that the following terms are well understood by those with ordinary knowledge in the technical field to which the present invention belongs, the following definitions are still described to better explain the present invention.

術語「包括」、「包含」、「具有」、「含有」或「涉及」及其在本文中的其它變體形式為包含性的(inclusive)或開放式的，且不排除其它未列舉的元素或方法步驟。The terms "include", "include", "have", "contain" or "involve" and other variants herein are inclusive or open-ended, and do not exclude other unlisted elements Or method steps.

如本文中所使用，術語「亞烷基」表示飽和二價烴基，較佳表示具有1、2、3、4、5或6個碳原子的飽和二價烴基，例如亞甲基、亞乙基、亞丙基或亞丁基。As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene , Propylene or butylene.

如本文中所使用，術語「烷基」定義為線性或支化飽和脂肪族烴。在一些實施方案中，烷基具有1至12個，例如1至6個碳原子。例如，如本文中所使用，術語「C_1-6 烷基」指1至6個碳原子的線性或支化的基團(例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基、叔丁基、正戊基、異戊基、新戊基或正己基)，其視情況經1或多個(諸如1至3個)適合的取代基如鹵素取代(此時該基團被稱作「鹵代烷基」)(例如CH₂ F、CHF₂ 、CF₃ 、CCl₃ 、C₂ F₅ 、C₂ Cl₅ 、CH₂ CF₃ 、CH₂ Cl或 -CH₂ CH₂ CF₃ 等)。術語「C_1-4 烷基」指1至4個碳原子的線性或支化的脂肪族烴鏈(即甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基或叔丁基)。As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C _1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which optionally has 1 or more (such as 1 to 3) suitable substituents such as Halogen substitution (in this case the group is called "haloalkyl") (e.g. CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl or -CH ₂ CH ₂ CF ₃ etc.). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).

如本文中所使用，術語「烯基」意指線性的或支化的單價烴基，其包含一個雙鍵，且具有2-6個碳原子(「C_2-6 烯基」)。所述烯基為例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基及4-甲基-3-戊烯基。當本發明的化合物含有亞烯基時，該化合物可以純E (異側(entgegen))形式、純Z (同側(zusammen))形式或其任意混合物形式存在。As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group that contains a double bond and has 2-6 carbon atoms ("C _2-6 alkenyl"). The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2 -Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenylene group, the compound may exist in the form of pure E (entgegen), pure Z (zusammen) or any mixture thereof.

如本文中所使用，術語「炔基」表示包含一個或多個三鍵的單價烴基，其優選具有2、3、4、5或6個碳原子，例如乙炔基或丙炔基。As used herein, the term "alkynyl" means a monovalent hydrocarbon group containing one or more triple bonds, which preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

如本文中所使用，術語「環烷基」指飽和的單環或多環(諸如雙環)烴環(例如單環，諸如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基，或雙環，包括螺環、稠合或橋連系統(諸如雙環[1.1.1]戊基、雙環[2.2.1]庚基、雙環[3.2.1]辛基或雙環[5.2.0]壬基、十氫化萘基等))，其視情況經1或多個(諸如1至3個)適合的取代基取代。所述環烷基具有3至15個碳原子。例如，術語「C_3-6 環烷基」指3至6個成環碳原子的飽和的單環或多環(諸如雙環)烴環(例如環丙基、環丁基、環戊基或環己基)，其視情況經1或多個(諸如1至3個)適合的取代基取代，例如甲基取代的環丙基。As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl Or bicyclic [5.2.0] nonyl, decalinyl, etc.)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclic ring) of 3 to 6 ring carbon atoms Hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.

如本文中所使用，術語「亞環烴基」、「環烴基」及「烴環」是指具有例如3-10個(適合地具有3-8個，更適合地具有3-6個)環碳原子的飽和(即，「亞環烷基」及「環烷基」)或不飽和的(即在環內具有一個或多個雙鍵及/或三鍵)單環或多環烴環，其包括但不限於(亞)環丙基(環)、(亞)環丁基(環)、(亞)環戊基(環)、(亞)環己基(環)、(亞)環庚基(環)、(亞)環辛基(環)、(亞)環壬基(環)、(亞)環己烯基(環)等。As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms saturated (ie, "cycloalkylene" and "cycloalkyl") or unsaturated (ie having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring, which Including but not limited to (ylidene) cyclopropyl (ring), (ylidene) cyclobutyl (ring), (ylidene) cyclopentyl (ring), (ylidene) cyclohexyl (ring), (ylidene) cycloheptyl ( (Cyclo), (ylidene)cyclooctyl (ring), (ylidene)cyclononyl (ring), (ylidene)cyclohexenyl (ring), etc.

如本文中所使用，術語「雜環基」、「亞雜環基」及「雜環」是指具有例如3-10個(適合地具有3-8個，更適合地具有3-6個)環原子、其中至少一個環原子是選自N、O及S的雜原子且其餘環原子是C的飽和(即，雜環烷基)或部分不飽和的(即在環內具有一個或多個雙鍵及/或三鍵)環狀基團。例如，「3-10員(亞)雜環(基)」是具有2-9個(如2、3、4、5、6、7、8或9個)環碳原子及獨立地選自N、O及S的一個或多個(例如1個、2個、3個或4個)雜原子的飽和或部分不飽和(亞)雜環(基)。亞雜環基及雜環(基)的實例包括但不限於：(亞)環氧乙烷基、(亞)氮丙啶基、(亞)氮雜環丁基(azetidinyl)、(亞)氧雜環丁基(oxetanyl)、(亞)四氫呋喃基、(亞)二氧雜環戊烯基(dioxolinyl)、(亞)吡咯烷基、(亞)吡咯烷酮基、(亞)咪唑烷基、(亞)吡唑烷基、(亞)吡咯啉基、(亞)四氫吡喃基、(亞)哌啶基、(亞)嗎啉基、(亞)二噻烷基(dithianyl)、(亞)硫嗎啉基、(亞)哌嗪基或(亞)三噻烷基(trithianyl)。所述基團也涵蓋雙環系統，包括螺環、稠合或橋連系統(諸如8-氮雜螺[4.5]癸烷、3,9-二氮雜螺[5.5]十一烷、2-氮雜雙環[2.2.2]辛烷等)。亞雜環基及雜環(基)可視情況經一個或多個(例如1個、2個、3個或4個)適合的取代基取代。As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to having, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remaining ring atoms are saturated (ie, heterocycloalkyl) or partially unsaturated (ie, have one or more in the ring Double bond and/or triple bond) cyclic group. For example, "3-10 member (ylidene) heterocycle (base)" means having 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and are independently selected from N One or more (for example, 1, 2, 3, or 4) heteroatoms of, O and S are saturated or partially unsaturated (ylidene) heterocycles (groups). Examples of heterocyclylene and heterocyclic (base) include but are not limited to: (ethylene oxide), (ethylene) aziridinyl, (azetidinyl), (ethylene) oxygen Oxetanyl (oxetanyl), (ylidene)tetrahydrofuranyl, (ylidene)dioxolinyl (dioxolinyl), (ylidene)pyrrolidinyl, (ylidene)pyrrolidonyl, (ylidene)imidazolidinyl, (ylidene) ) Pyrazolidinyl, (ylidene) pyrrolinyl, (ylidene) tetrahydropyranyl, (ylidene) piperidinyl, (ylidene) morpholinyl, (ylidene) dithialyl (dithianyl), (ylidene) Thiomorpholinyl, (ylidene)piperazinyl, or (trithianyl). The group also encompasses bicyclic ring systems, including spirocyclic, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane etc.). The heterocyclylene and heterocyclic (base) may optionally be substituted with one or more (for example, 1, 2, 3, or 4) suitable substituents.

如本文中所使用，術語「(亞)芳基」及「芳環」指具有共軛π電子系統的全碳單環或稠合環多環芳族基團。例如，如本文中所使用，術語「C_6-10 (亞)芳基」及「C_6-10 芳環」意指含有6至10個碳原子的芳族基團，諸如(亞)苯基(苯環)或(亞)萘基(萘環)。(亞)芳基及芳環視情況經1或多個(諸如1至3個)適合的取代基(例如鹵素、-OH、-CN、-NO₂ 、C_1-6 烷基等)取代。As used herein, the terms "(arylene)" and "aromatic ring" refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the terms "C _6-10 (arylene)" and "C _6-10 aromatic ring" mean aromatic groups containing 6 to 10 carbon atoms, such as (phenylene) (Benzene ring) or ()naphthylene (naphthalene ring). The ()arylene group and the aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

如本文中所使用，術語「(亞)雜芳基」及「雜芳環」指單環、雙環或三環芳族環系，其具有5、6、8、9、10、11、12、13或14個環原子，特別是1或2或3或4或5或6或9或10個碳原子，且其包含至少一個可以相同或不同的雜原子(該雜原子是例如氧、氮或硫)，並且，另外在每一種情況下可為苯并稠合的。特別地，「(亞)雜芳基」或「雜芳環」選自(亞)噻吩基、(亞)呋喃基、(亞)吡咯基、(亞)噁唑基、(亞)噻唑基、(亞)咪唑基、(亞)吡唑基、(亞)異噁唑基、(亞)異噻唑基、(亞)噁二唑基、(亞)三唑基、(亞)噻二唑基等，以及它們的苯并衍生物；或(亞)吡啶基、(亞)噠嗪基、(亞)嘧啶基、(亞)吡嗪基、(亞)三嗪基等，以及它們的苯并衍生物。As used herein, the terms "(ylidene)heteroaryl" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or Sulfur), and, in addition, may be benzo-fused in each case. In particular, "(ylidene)heteroaryl" or "heteroaromatic ring" is selected from (ylidene)thienyl, (ylidene)furyl, (ylidene)pyrrolyl, (ylidene)oxazolyl, (ylidene)thiazolyl, (Sub)imidazolyl, (sub)pyrazolyl, (sub)isoxazolyl, (sub)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl Etc., and their benzo derivatives; or (ylidene) pyridinyl, (ylidene) pyridazinyl, (ylidene) pyrimidinyl, (ylidene) pyrazinyl, (ylidene) triazinyl, etc., and their benzo derivative.

如本文中所使用，術語「芳烷基」較佳表示芳基或雜芳基取代的烷基，其中該芳基、雜芳基及烷基如本文中所定義。通常，所述芳基可具有6-14個碳原子，所述雜芳基可具有5-14個環原子，並且所述烷基可具有1-6個碳原子。示例性芳烷基包括但不限於苄基、苯基乙基、苯基丙基、苯基丁基。As used herein, the term "aralkyl" preferably refers to an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein. Generally, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

如本文中所使用，術語「鹵代」或「鹵素」基團定義為包括F、Cl、Br或I。As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

如本文中所使用，術語「含氮雜環」指飽和或不飽和的單環或雙環基團，其在環中具有2、3、4、5、6、7、8、9、10、11、12或13個碳原子及至少一個氮原子，其還可視情況包含一個或多個(例如一個、兩個、三個或四個)選自N、O、C=O、S、S=O及S(=O)₂ 的環成員，其通過該含氮雜環中的氮原子以及任一其餘環原子與分子的其餘部分連接，該含氮雜環視情況為苯并稠合的，並且較佳通過該含氮雜環中的氮原子以及所稠合的苯環中的任一碳原子與分子的其餘部分連接。As used herein, the term "nitrogen-containing heterocyclic ring" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 in the ring , 12 or 13 carbon atoms and at least one nitrogen atom, which may also include one or more (for example, one, two, three or four) selected from N, O, C=O, S, S=O as appropriate And S(=O) ₂ ring members, which are connected to the rest of the molecule through the nitrogen atom in the nitrogen-containing heterocyclic ring and any remaining ring atoms. The nitrogen-containing heterocyclic ring is optionally benzo-fused and relatively Preferably, it is connected to the rest of the molecule through the nitrogen atom in the nitrogen-containing heterocyclic ring and any carbon atom in the fused benzene ring.

術語「取代」指所指定的原子上的一個或多個(例如一個、兩個、三個或四個)氫被從所指出的基團的選擇代替，條件是未超過所指定的原子在當前情況下的正常原子價並且該取代形成穩定的化合物。取代基及/或變數的組合僅僅當這種組合形成穩定的化合物時才是允許的。The term "substitution" means that one or more (for example, one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is present In the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are only permitted when such combinations form stable compounds.

如果取代基被描述為「視情況經取代」，則取代基可(1)未經取代或(2)經取代。如果取代基的碳被描述為視情況經取代基列表中的一個或多個取代，則碳上的一個或多個氫(至存在的任何氫的程度)可單獨及/或一起經獨立地選擇的任選的取代基替代。如果取代基的氮被描述為視情況經取代基列表中的一個或多個取代，則氮上的一個或多個氫(至存在的任何氫的程度)可各自經獨立地選擇的任選的取代基替代。If a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently selected individually and/or together The optional substituents are substituted. If the nitrogen of a substituent is described as optionally substituted by one or more of the substituent list, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional Substituent substitution.

如果取代基被描述為「獨立地選自」一組，則各取代基獨立於另一者被選擇。因此，各取代基可與另一(其他)取代基相同或不同。If substituents are described as being "independently selected from" a group, then each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.

如本文中所使用，術語「一個或多個」意指在合理條件下的1個或超過1個，例如2個、3個、4個、5個或10個。As used herein, the term "one or more" means one or more than one under reasonable conditions, such as two, three, four, five, or ten.

除非指明，否則如本文中所使用，取代基的連接點可來自取代基的任意適宜位置。Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

當取代基的鍵顯示為穿過環中連接兩個原子的鍵時，則這樣的取代基可鍵連至該可取代的環中的任一成環原子。When the bond of a substituent is shown as a bond connecting two atoms through a ring, then such substituent may be bonded to any ring-forming atom in the substitutable ring.

本發明還包括所有藥學上可接受的同位素標記的化合物，其與本發明的化合物相同，除了一個或多個原子被具有相同原子序數但原子品質或質量數不同於在自然界中佔優勢的原子品質或質量數的原子替代。適合包含入本發明的化合物中的同位素的實例包括(但不限於)氫的同位素(例如氘(² H)、氚(³ H))；碳的同位素(例如¹¹ C、¹³ C及¹⁴ C)；氯的同位素(例如³⁶ Cl)；氟的同位素(例如¹⁸ F)；碘的同位素(例如¹²³ I及¹²⁵ I)；氮的同位素(例如¹³ N及¹⁵ N)；氧的同位素(例如¹⁵ O、¹⁷ O及¹⁸ O)；磷的同位素(例如³² P)；及硫的同位素(例如³⁵ S)。某些同位素標記的本發明的化合物(例如摻入放射性同位素的那些)可用於藥物及/或底物組織分佈研究(例如分析)中。放射性同位素氚(即³ H)及碳-14(即¹⁴ C)因易於摻入且容易檢測而特別可用於該目的。用正電子發射同位素(例如¹¹ C、¹⁸ F、¹⁵ O及¹³ N)進行取代可在正電子發射斷層顯像術(PET)研究中用於檢驗底物受體佔據情況。經同位素標記的本發明的化合物可通過與描述於隨附路線及/或實施例及製備中的那些類似的方法通過使用適當的經同位素標記的試劑代替之前採用的非標記的試劑來製備。本發明的藥學上可接受的溶劑合物包括其中結晶溶劑可經同位素取代的那些，例如，D₂ O、丙酮-d₆ 或DMSO-d₆ 。The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic quality or mass number is different from the atomic quality predominant in nature. Or atomic substitution of mass number. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (such as deuterium ( ² H), tritium ( ³ H)); isotopes of carbon (such as ¹¹ C, ¹³ C, and ¹⁴ C) ; Isotopes of chlorine (such as ³⁶ Cl); isotopes of fluorine (such as ¹⁸ F); isotopes of iodine (such as ¹²³ I and ¹²⁵ I); isotopes of nitrogen (such as ¹³ N and ¹⁵ N); isotopes of oxygen (such as ¹⁵ O , ¹⁷ O and ¹⁸ O); phosphorus isotopes (such as ³² P); and sulfur isotopes (such as ³⁵ S). Certain isotopically labeled compounds of the present invention (such as those incorporating radioisotopes) can be used in drug and/or substrate tissue distribution studies (such as analysis). The radioisotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. Substitution with positron emission isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to test substrate receptor occupancy in positron emission tomography (PET) studies. The isotopically-labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations by using appropriate isotopically-labeled reagents instead of the previously used non-labeled reagents. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be replaced by an isotope, for example, D ₂ O, acetone- d ₆ or DMSO- d ₆ .

術語「立體異構體」表示由於至少一個不對稱中心形成的異構體。在具有一個或多個(例如一個、兩個、三個或四個)不對稱中心的化合物中，其可產生外消旋混合物、單一對映異構體、非對映異構體混合物及單獨的非對映異構體。特定個別分子也可以幾何異構體(順式/反式)存在。類似地，本發明的化合物可以兩種或更多種處於快速平衡的結構不同的形式的混合物(通常稱作互變異構體)存在。互變異構體的代表性實例包括酮-烯醇互變異構體、苯酚-酮互變異構體、亞硝基-肟互變異構體、亞胺-烯胺互變異構體等。要理解，本申請案的範圍涵蓋所有這樣的以任意比例(例如60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)的異構體或其混合物。The term "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (for example, one, two, three or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It should be understood that the scope of this application covers all such cases in arbitrary proportions (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) isomers or mixtures thereof.

本文中可使用實線(

)、實楔形(

)或虛楔形(

)描繪本發明的化合物的化學鍵。使用實線以描繪鍵連至不對稱碳原子的鍵欲表明，包括該碳原子處的所有可能的立體異構體(例如，特定的對映異構體、外消旋混合物等)。使用實或虛楔形以描繪鍵連至不對稱碳原子的鍵欲表明，存在所示的立體異構體。當存在於外消旋混合物中時，使用實及虛楔形以定義相對立體化學，而非絕對立體化學。除非另外指明，否則本發明的化合物意欲可以立體異構體(其包括順式及反式異構體、光學異構體(例如R及S對映異構體)、非對映異構體、幾何異構體、旋轉異構體、構象異構體、阻轉異構體及其混合物)的形式存在。本發明的化合物可表現一種以上類型的異構現象，且由其混合物(例如外消旋混合物及非對映異構體對)組成。The solid line (

), solid wedge (

) Or virtual wedge (

) Depicts the chemical bonds of the compounds of the invention. The use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, use real and imaginary wedges to define relative stereochemistry, rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof) exist. The compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).

本發明涵蓋本發明的化合物的所有可能的結晶形式或多晶型物，其可為單一多晶型物或多於一種多晶型物的任意比例的混合物。The present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

還應當理解，本發明的某些化合物可以游離形式存在用於治療，或適當時，以其藥學上可接受的衍生物形式存在。在本發明中，藥學上可接受的衍生物包括但不限於，藥學上可接受的鹽、酯、溶劑合物、N-氧化物、代謝物或前藥，在將它們向需要其的患者給藥後，能夠直接或間接提供本發明的化合物或其代謝物或殘餘物。因此，當在本文中提及「本發明的化合物」時，也意在涵蓋化合物的上述各種衍生物形式。It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, when appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which can be administered to patients in need thereof. After medication, the compound of the present invention or its metabolites or residues can be directly or indirectly provided. Therefore, when referring to the "compounds of the present invention" herein, it is also intended to cover the above-mentioned various derivative forms of the compounds.

本發明的化合物的藥學上可接受的鹽包括其酸加成鹽及鹼加成鹽。The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

適合的酸加成鹽由形成藥學可接受鹽的酸來形成。實例包括乙酸鹽、己二酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、硼酸鹽、樟腦磺酸鹽、檸檬酸鹽、環己胺磺酸鹽、乙二磺酸鹽、乙磺酸鹽、甲酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸鹽、六氟磷酸鹽、海苯酸鹽、鹽酸鹽/氯化物、氫溴酸鹽/溴化物、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲磺酸鹽、甲基硫酸鹽、萘甲酸鹽(naphthylate)、2-萘磺酸鹽、煙酸鹽、硝酸鹽、乳清酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、焦谷胺酸鹽、糖二酸鹽、硬脂酸鹽、丁二酸鹽、單寧酸鹽、酒石酸鹽、甲苯磺酸鹽、三氟乙酸鹽及昔萘酸鹽(xinofoate)。Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citric acid Salt, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, sea salt Benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate Acid salt, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxylate Naphthalate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, Trifluoroacetate and xinofoate (xinofoate).

適合的鹼加成鹽由形成藥學可接受鹽的鹼來形成。實例包括鋁鹽、精胺酸鹽、苄星青黴素鹽、鈣鹽、膽鹼鹽、二乙胺鹽、二乙醇胺鹽、甘胺酸鹽、離胺酸鹽、鎂鹽、葡甲胺鹽、乙醇胺鹽、鉀鹽、鈉鹽、胺丁三醇鹽及鋅鹽。Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, ethanolamine Salt, potassium salt, sodium salt, tromethamine salt and zinc salt.

適合的鹽的綜述參見Stahl及Wermuth的「Handbook of Pharmaceutical Salts: Properties, Selection, and Use」 (Wiley-VCH, 2002)。用於製備本發明的化合物的藥學上可接受的鹽的方法為本發明所屬技術領域中具有通常知識者已知的。For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). The method for preparing the pharmaceutically acceptable salt of the compound of the present invention is known to those having ordinary knowledge in the technical field to which the present invention belongs.

如本文中所使用，術語「酯」意指衍生自本申請中各個通式化合物的酯，其包括生理上可水解的酯(可在生理條件下水解以釋放游離酸或醇形式的本發明的化合物)。本發明的化合物本身也可以是酯。As used herein, the term "ester" means an ester derived from each compound of the general formula in this application, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention Compound). The compound of the present invention may itself be an ester.

本發明的化合物可以溶劑合物(較佳水合物)的形式存在，其中本發明的化合物包含作為該化合物晶格的結構要素的極性溶劑，特別是例如水、甲醇或乙醇。極性溶劑特別是水的量可以化學計量比或非化學計量比存在。The compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the compound's crystal lattice, especially, for example, water, methanol or ethanol. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

本發明所屬技術領域中具有通常知識者會理解，由於氮需要可用的孤對電子來氧化成氧化物，因此並非所有的含氮雜環都能夠形成N- 氧化物；本發明所屬技術領域中具有通常知識者會識別能夠形成N- 氧化物的含氮雜環。本發明所屬技術領域中具有通常知識者還會認識到叔胺能夠形成N- 氧化物。用於製備雜環及叔胺的N- 氧化物的合成方法是本發明所屬技術領域中具有通常知識者熟知的，包括用過氧酸如過氧乙酸及間氯過氧苯甲酸(MCPBA)、過氧化氫、烷基過氧化氫如叔丁基過氧化氫、過硼酸鈉及雙環氧乙烷(dioxirane)如二甲基雙環氧乙烷來氧化雜環及叔胺。這些用於製備N- 氧化物的方法已在文獻中得到廣泛描述及綜述，參見例如：T. L. Gilchrist,Comprehensive Organic Synthesis , vol. 7, pp 748-750；A. R. Katritzky及A. J. Boulton, Eds., Academic Press；以及G. W. H. Cheeseman及E. S. G. Werstiuk，Advances in Heterocyclic Chemistry , vol. 22, pp 390-392, A. R. Katritzky及A. J. Boulton, Eds., Academic Press。Those with ordinary knowledge in the technical field of the present invention will understand that since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles can form N- oxides; Usually the knowledgeable person will recognize nitrogen-containing heterocycles that can form N- oxides. Those skilled in the art to which the present invention pertains will also recognize that tertiary amines can form N- oxides. The synthetic methods for the preparation of heterocyclic and tertiary amine N- oxides are well known to those with ordinary knowledge in the technical field of the present invention, including the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), Hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane to oxidize heterocycles and tertiary amines. These methods for the preparation of N- oxides have been widely described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis , vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press ; And GWH Cheeseman and ESG Werstiuk, Advances in Heterocyclic Chemistry , vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

在本發明的範圍內還包括本發明的化合物的代謝物，即在給藥本發明的化合物時體內形成的物質。這樣的產物可由例如被給藥的化合物的氧化、還原、水解、醯胺化、脫醯胺化、酯化、酶解等產生。因此，本發明包括本發明的化合物的代謝物，包括通過使本發明的化合物與哺乳動物接觸足以產生其代謝產物的時間的方法製得的化合物。Also included within the scope of the present invention are metabolites of the compounds of the present invention, that is, substances formed in the body when the compounds of the present invention are administered. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amination, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolites.

本發明在其範圍內進一步包括本發明的化合物的前藥，其為自身可具有較小藥理學活性或無藥理學活性的本發明的化合物的某些衍生物當被給藥至身體中或其上時可通過例如水解裂解轉化成具有期望活性的本發明的化合物。通常這樣的前藥會是所述化合物的官能團衍生物，其易於在體內轉化成期望的治療活性化合物。關於前藥的使用的其他資訊可參見「Pro-drugs as Novel Delivery Systems」，第14卷，ACS Symposium Series (T. Higuchi及V. Stella)。本發明的前藥可例如通過用本發明所屬技術領域中具有通常知識者已知作為「前-部分(pro-moiety) (例如『Design of Prodrugs』，H. Bundgaard (Elsevier, 1985)中所述)」的某些部分替代本發明的化合物中存在的適當官能團來製備。The present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity when administered to or on the body It can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage. Usually such prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo. For additional information on the use of prodrugs, see "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be used, for example, as described in "Pro-moiety" (for example, "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) known to those with ordinary knowledge in the technical field of the present invention. )" is prepared by replacing appropriate functional groups present in the compounds of the present invention.

本發明還涵蓋含有保護基的本發明的化合物。在製備本發明的化合物的任何過程中，保護在任何有關分子上的敏感基團或反應基團可能是必需的及/或期望的，由此形成本發明的化合物的化學保護的形式。這可以通過常規的保護基實現，例如，在T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991中所述的那些保護基，這些參考文獻通過援引加入本文。使用本領域已知的方法，在適當的後續階段可以移除保護基。The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.

術語「約」是指在所述數值的±10%範圍內，較佳±5%範圍內，更佳±2%範圍內。The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

「非酒精性脂肪性肝炎(NASH)」是與飲酒無關的、特徵在於肝細胞脂肪性改變、伴隨小葉內炎症的肝病。"Non-alcoholic steatohepatitis (NASH)" is a liver disease that is not related to alcohol consumption and is characterized by fatty changes in liver cells and accompanied by inflammation in the lobules.

NASH類似於酒精性肝病，但在幾乎不飲酒或不飲酒的人中發生。NASH的主要特徵在於肝中的脂肪與炎症及損害。具有NASH的大部分人感覺良好並且沒有意識到他們存在肝問題。儘管如此，NASH可能是嚴重的且可以導致肝硬化，其中肝永久性地損傷及瘢痕化，且不再能夠正常起作用。NASH is similar to alcoholic liver disease, but it occurs in people who hardly or do not drink alcohol. The main characteristics of NASH are fat in the liver and inflammation and damage. Most people with NASH feel good and don't realize they have liver problems. Nonetheless, NASH can be severe and can lead to cirrhosis, where the liver is permanently damaged and scarred and can no longer function normally.

非酒精性脂肪性肝病(NAFLD)是常見於慢性肝病個體中的脂肪肝病。過量的肝脂肪可以導致肝臟併發症。儘管與酒精無關，但是這些病症可能與肥胖、膳食及其它與健康相關的問題有關。Non-alcoholic fatty liver disease (NAFLD) is a fatty liver disease commonly seen in individuals with chronic liver disease. Excess liver fat can cause liver complications. Although not related to alcohol, these conditions may be related to obesity, diet, and other health-related issues.

具有升高的肝酶的個體及/或具有脂肪肝的個體(例如根據超聲或脂肪肝指標確定)被視為具有NASH或NAFLD。酶、脂肪或脂肪肝指標降低是改善或校正病症的指示物。Individuals with elevated liver enzymes and/or individuals with fatty liver (for example, as determined by ultrasound or fatty liver indicators) are considered to have NASH or NAFLD. Enzyme, fat, or fatty liver index reduction is an indicator to improve or correct the condition.

術語「有效量」是指在施用條件下足以達到所需治療效果的量，例如該量足以降低空腹血糖(FPG)，減輕體重，降低血脂如膽固醇及甘油三酯(TG)，降低肝酶，提高高密度脂蛋白膽固醇(HDL-C)水準及降低血壓。例如，施用於患有表現出、患有或易患脂肪性肝病及/或脂肪性肝炎(例如NASH或NAFLD)的患者的式(I)的化合物的「有效量」是這樣的量，其導致病理學症狀，疾病進展，與之相關的生理狀況改善或誘導對前述疾病進行的抵抗力。The term "effective amount" refers to an amount sufficient to achieve the desired therapeutic effect under the conditions of administration, for example, the amount is sufficient to lower fasting blood glucose (FPG), reduce body weight, lower blood lipids such as cholesterol and triglycerides (TG), lower liver enzymes, Improve high-density lipoprotein cholesterol (HDL-C) levels and lower blood pressure. For example, the "effective amount" of the compound of formula (I) administered to a patient who exhibits, suffers from, or is susceptible to fatty liver disease and/or steatohepatitis (such as NASH or NAFLD) is an amount that results in Pathological symptoms, disease progression, and related physiological conditions improve or induce resistance to the aforementioned diseases.

如本文所用的術語「預防」是指預先施用藥物以避免或預防疾病或病症的一種或多種症狀的出現。醫學領域的通常知識者認識到術語「預防」不是絕對術語。在醫學領域中，應理解為預防性施用藥物以基本上減少病症的可能性或嚴重性或病症的症狀，這是本公開內容中意圖的意義。預防分為一級預防(以防止疾病的發展)及二級預防(由此疾病已經發展並且患者受到保護以防止該過程的惡化)。The term "prevention" as used herein refers to pre-administration of drugs to avoid or prevent the appearance of one or more symptoms of a disease or condition. Common knowledge in the medical field recognizes that the term "prevention" is not an absolute term. In the medical field, it should be understood that prophylactic administration of drugs to substantially reduce the likelihood or severity of the disorder or the symptoms of the disorder is the intended meaning in the present disclosure. Prevention is divided into primary prevention (to prevent the development of the disease) and secondary prevention (therefore the disease has developed and the patient is protected to prevent the progress of the process).

除非另外說明，否則如本文中所使用，術語「治療(treating)」意指逆轉、減輕、抑制這樣的術語所應用的病症或病況或者這樣的病症或病況的一或多種症狀的進展，或預防這樣的病症或病況或者這樣的病症或病況的一或多種症狀。Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, inhibiting the disease or condition to which such term is applied or the progression of one or more symptoms of such a disease or condition, or preventing Such a disorder or condition or one or more symptoms of such a disorder or condition.

在一些實施方案中，治療導致至少一種可測量的脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)身體症狀的改善，例如體重減輕、虛弱或疲勞。在其他實施方案中，治療導致脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)的至少一種臨床參數或表現的改善，例如，異常肝臟脂肪積聚、肝酶的異常水準、脂肪變性(如以含有脂肪的肝細胞的百分數評估或通過圖像分析分級)、膠原堆積(如以指示膠原蛋白的天狼星紅的肝組織染色陽性的百分數評估)或氣球樣變(如以腫脹肝細胞的百分數評估)。In some embodiments, the treatment results in an improvement in at least one measurable fatty liver disease and/or steatohepatitis (e.g., NAFLD and/or NASH) physical symptoms, such as weight loss, weakness, or fatigue. In other embodiments, the treatment results in improvement of at least one clinical parameter or performance of fatty liver disease and/or steatohepatitis (eg NAFLD and/or NASH), for example, abnormal liver fat accumulation, abnormal levels of liver enzymes, steatosis (E.g., evaluated by the percentage of fatty liver cells or graded by image analysis), collagen accumulation (e.g., evaluated by the percentage of positive liver tissue staining with Sirius red that indicates collagen) or ballooning (e.g., swollen liver cells Percentage evaluation).

在其他實施方案中，通過例如穩定可測量的症狀或一組症狀(例如疲勞，體重減輕或虛弱)來在身體上，或者通過例如穩定可測量的參數，如肝臟中的異常脂肪積累、肝酶的異常水準、肝臟活組織檢查中的異常表現、脂肪變性、膠原堆積或氣球樣變在臨床/生理學上，或全部兩者，治療導致脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)進展的減少、抑制或減緩。在另一個實施方案中，治療還可以導致在疾病或病症完全表現出來之前避免脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)的原因及/或作用或臨床表現，或由脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)引起的症狀之一。In other embodiments, on the body by, for example, stabilizing a measurable symptom or set of symptoms (e.g., fatigue, weight loss, or weakness), or by stabilizing, for example, a measurable parameter such as abnormal fat accumulation in the liver, liver enzymes The abnormal level of liver biopsy, abnormal manifestations in liver biopsy, steatosis, collagen accumulation or ballooning are clinically/physiologically, or both, the treatment of fatty liver disease and/or steatohepatitis (such as NAFLD and/ Or NASH) reduction, inhibition or slowing down of progress. In another embodiment, treatment can also lead to avoiding the causes and/or effects or clinical manifestations of fatty liver disease and/or steatohepatitis (such as NAFLD and/or NASH) before the disease or condition is fully manifested, or caused by fat One of the symptoms caused by liver disease and/or steatohepatitis (such as NAFLD and/or NASH).

在一些實施方案中，治療導致患有脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)的患者的存活率或存活時間的增加。在一些實施方案中，治療導致患有脂肪性肝病及/或脂肪性肝炎(例如(NAFLD及/或NASH)的患者需要肝移植的可能性降低。在其他實施方案中，治療導致消除對脂肪性肝病及/或脂肪性肝炎(例如NAFLD及/或NASH)患者進行肝移植的需要。In some embodiments, treatment results in an increase in the survival rate or survival time of patients with fatty liver disease and/or steatohepatitis (eg, NAFLD and/or NASH). In some embodiments, treatment results in patients suffering from fatty liver disease and/or steatohepatitis (e.g. (NAFLD and/or NASH)) being less likely to require liver transplantation. In other embodiments, treatment results in elimination of fatty liver disease. The need for liver transplantation for patients with liver disease and/or steatohepatitis (such as NAFLD and/or NASH).

如本文所使用的「個體」包括人或非人動物。示例性人個體包括患有疾病(例如本文所述的疾病)的人個體(稱為患者)或正常個體。本發明中「非人動物」包括所有脊椎動物，例如非哺乳動物(例如鳥類、兩棲動物、爬行動物)及哺乳動物，例如非人靈長類、家畜及/或馴化動物(例如綿羊、犬、貓、奶牛、豬等)。"Individual" as used herein includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs, Cats, cows, pigs, etc.).

具體實施方式 在一些實施方案中，本發明提供預防、緩解及/或治療脂肪性肝病及/或脂肪性肝炎的方法，其包括向需要其的個體給藥有效量的式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥：

式(I) 其中： X及Y各自獨立地選自直接鍵、C(=O)、O、S(=O)_i 及NR； R選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、飽和或部分不飽和的C_3-10 環烴基、飽和或部分不飽和的3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基，該環烴基及雜環基中至多2個環成員為C(=O)；環A及環B各自獨立地選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)，條件是當環B為含有氮原子的雜環時，環B不通過該氮原子與X連接；環C選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)；環D不存在或者選自飽和或部分不飽和的C_3-10 烴環、飽和或部分不飽和的3-10員雜環、C_6-10 芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)；環E選自

、

及

、乙醯基、

、

、-C(=O)-(C_1-6 亞烷基)_n -CF₃ 、-C(=O)-(C_1-6 亞烷基)_n -CN、 -C(=O)-(飽和或部分不飽和的C_3-10 環烴基)、-NHC(=O)-(飽和或部分不飽和的C_3-10 環烴基)、-C(=O)-(飽和或部分不飽和的3-10員雜環基)、 -C(=O)-C_1-6 亞烷基-(飽和或部分不飽和的3-10員雜環基)、-C(=O)-(5-14員雜芳基)、-C(=O)-C_1-6 亞烷基-NH(C_1-6 烷基)、-C(=O)-C_1-6 亞烷基 -N(C_1-6 烷基)₂ 、N-甲基哌嗪取代的乙醯基、-S(=O)₂ R^1a 、-P(=O)R^1a R^1b 、

、

及

時，環C不是5員雜芳環；並且當R¹ 及R¹⁰ 中一個為H且另一個為H或乙醯基時，環D不存在； R^1a 及R^1b 各自獨立地選自H、鹵素、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-C(=O)R⁵ 、-OC(=O)R⁵ 、-C(=O)OR⁵ 、-OR⁵ 、 -SR⁵ 、-S(=O)R⁵ 、-S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、-NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、-NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、-C_1-6 亞烷基-NR⁵ R⁶ 、-C_1-6 亞烷基-OR⁵ 及-O-C_1-6 亞烷基-NR⁵ R⁶ ，條件是當R^1a 及R^1b 之一為正丙基時，另一個不為H；或者R^1a 及R^1b 連同其所連接的原子共同構成3-12員雜環或雜芳環； R² 、R³ 、R⁴ 、R⁷ 、R⁸ 、R⁹ 及R¹⁰ 在每次出現時各自獨立地選自H、鹵素、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、 -C(=O)R⁵ 、-OC(=O)R⁵ 、-C(=O)OR⁵ 、-OR⁵ 、-SR⁵ 、-S(=O)R⁵ 、 -S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、-NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、 -NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、-C_1-6 亞烷基-NR⁵ R⁶ 、-C_1-6 亞烷基-O(P=O)(OH)₂ 及-O-C_1-6 亞烷基-NR⁵ R⁶ ；上述烷基、亞烷基、烯基、炔基、環烴基、烴環、雜環基、雜環、芳基、芳環、雜芳基、雜芳環及芳烷基在每次出現時各自視情況經一個或多個獨立地選自下列的取代基取代：鹵素、羥基、氧代、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、=N-OR⁵ 、 -C(=NH)NH₂ 、-C(=O)R⁵ 、-OC(=O)R⁵ 、-C(=O)OR⁵ 、-OR⁵ 、-SR⁵ 、 -S(=O)R⁵ 、-S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、-NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、-NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、 -C_1-6 亞烷基-NR⁵ R⁶ 及-O-C_1-6 亞烷基-NR⁵ R⁶ ，該烷基、環烴基、雜環基、芳基、雜芳基及芳烷基進一步視情況經一個或多個獨立地選自下列的取代基取代：鹵素、羥基、氧代、胺基、氰基、硝基、C_1-6 烷基、C_3-6 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基； R⁵ 及R⁶ 在每次出現時各自獨立地選自H、C_1-6 烷基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基； m在每次出現時各自獨立地為0、1、2或3的整數； n為0、1或2的整數； i為0、1或2的整數；並且 g為0、1、2、3或4的整數；其中該脂肪性肝病較佳為酒精性脂肪性肝病(AFLD)或非酒精性脂肪性肝病(NAFLD)，該脂肪性肝炎較佳為酒精性脂肪性肝炎(ASH)或非酒精性脂肪性肝炎(NASH)。 DETAILED DESCRIPTION In some embodiments, the present invention provides a method for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (I) or Its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:

Formula (I) wherein: X and Y are each independently selected from direct bond, C(=O), O, S(=O) _i and NR; R is selected from H, C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl Group and C _6-12 aralkyl group, in the cyclic hydrocarbon group and heterocyclic group, at most two ring members are C(=O); ring A and ring B are each independently selected from saturated or partially unsaturated C _3-10 Hydrocarbon ring, saturated or partially unsaturated 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring, in which at most 2 ring members are C(=O), The condition is that when ring B is a heterocyclic ring containing a nitrogen atom, ring B is not connected to X through the nitrogen atom; ring C is selected from a saturated or partially unsaturated C _3-10 hydrocarbon ring, a saturated or partially unsaturated 3- 10-membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); ring D does not exist or is selected from saturated or partially non-existent Saturated C _3-10 hydrocarbon ring, saturated or partially unsaturated 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring. Up to 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); ring E is selected from

,

and

, Acetyl,

,

and

When, ring C is not a 5-membered heteroaromatic ring; and when one of R ¹ and R ¹⁰ is H and the other is H or acetyl, ring D does not exist; R ^1a and R ^1b are each independently selected from H, Halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _{6- 10} aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O) -NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-OR ⁵ and -OC _1-6 alkylene-NR ⁵ R ⁶ , provided that R ^When one of ^1a and R ^1b is n-propyl, the other is not H; or R ^1a and R ^1b together with the atoms to which they are connected form a 3-12 member heterocyclic or heteroaromatic ring; R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from H, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O )R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ ,- S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 Alkylene-O(P=O)(OH) ₂ and -OC _1-6 Alkylene-NR ⁵ R ⁶ ; The above-mentioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, hetero Cyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic and aralkyl groups are each substituted with one or more substituents independently selected from the following when each occurrence: halogen, hydroxy, Oxo, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-10 members Heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(= O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ ,- NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 alkylene -NR ⁵ R ⁶ , the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group are further optionally substituted with one or more substituents independently selected from the following: halogen, hydroxyl, oxygen Generation, amino, cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl and C _{6 -12} aralkyl; R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-10 cyclic hydrocarbon group, 3-10 membered heterocyclic group, C _6-10 aryl at each occurrence Group, 5-14 membered heteroaryl group and C _6-12 aralkyl group; m is each independently an integer of 0, 1, 2 or 3 at each occurrence; n is an integer of 0, 1 or 2; i is An integer of 0, 1 or 2; and g is an integer of 0, 1, 2, 3 or 4; wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD), The steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).

在較佳的實施方案中，X及Y各自獨立地選自直接鍵、C(=O)、O、S、S(=O)、S(=O)₂ 、NH及NCH₃ ，並且較佳地，X及Y中至少一個為直接鍵。In a preferred embodiment, X and Y are each independently selected from direct bond, C(=O), O, S, S(=O), S(=O) ₂ , NH and NCH ₃ , and preferably Ground, at least one of X and Y is a direct bond.

在較佳的實施方案中，環A及環B中至少一個選自飽和或部分不飽和的3-10員雜環及5-14員雜芳環，該雜環中至多2個環成員為C(=O)。In a preferred embodiment, at least one of ring A and ring B is selected from a saturated or partially unsaturated 3-10 membered heterocyclic ring and a 5-14 membered heteroaromatic ring, in which at most 2 ring members are C (=O).

在一些實施方案中，

為

或

，較佳為

、

、

或

，以上基團通過#或##標記的兩個位置之一與X連接，並且另一位置與R¹ 連接，其中---- 表示單鍵或雙鍵且相鄰的鍵不同時為雙鍵； Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 、Z⁷ 、Z⁸ 及Z⁹ 在每次出現時各自獨立地選自C、CR⁹ 、C(R⁹ )₂ 、CR¹⁰ 、C(R¹⁰ )₂ 、C(=O)、N、NR⁹ 、NR¹⁰ 、O及S；較佳地，Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 、Z⁷ 、Z⁸ 及Z⁹ 在每次出現時各自獨立地選自C、CH、CF、CCl、CCH₃ 、CH₂ 、C(CH₃ )₂ 、C-OCH₃ 、C(=O)、N、NH、NCH₃ 、NCH₂ CH₃ 、NCH(CH₃ )₂ 、NCH=CH₂ 、NCH₂ F、NCHF₂ 、NCH₂ CHF₂ 、NC(=O)CH₃ 、NCH₂ OH、NCH₂ OMe、NCH₂ CH₂ OMe、NCH₂ -O(P=O)(OH)₂ 、

、

、

、

、

、

、

、NCH₂ CH₂ -N(CH₃ )₂ 、O及S； j為0、1、2、3或4；並且條件是Z¹ -Z⁹ 中的至多兩個基團同時為C(=O)，並且與X連接的原子不是氮原子。In some embodiments,

for

or

, Preferably

,

or

, The above group is connected to X through one of the two positions marked with # or ##, and the other position is connected to R¹ connection, among them---- Indicates single or double bonds and adjacent bonds are not double bonds at the same time; Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ ,Z⁷ ,Z⁸ And Z⁹ Each occurrence is independently selected from C, CR⁹ , C(R⁹ )₂ , CR¹⁰ , C(R¹⁰ )₂ , C(=O), N, NR⁹ , NR¹⁰ , O and S; preferably, Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ ,Z⁷ ,Z⁸ And Z⁹ Each occurrence is independently selected from C, CH, CF, CCl, CCH₃ , CH₂ , C(CH₃ )₂ , C-OCH₃ , C(=O), N, NH, NCH₃ , NCH₂ CH₃ , NCH(CH₃ )₂ , NCH=CH₂ , NCH₂ F, NCHF₂ , NCH₂ CHF₂ , NC(=O)CH₃ , NCH₂ OH, NCH₂ OMe, NCH₂ CH₂ OMe, NCH₂ -O(P=O)(OH)₂ ,

,

, NCH₂ CH₂ -N(CH₃ )₂ , O and S; j is 0, 1, 2, 3 or 4; and The condition is Z¹ -Z⁹ At most two groups in are C (=O) at the same time, and the atom connected to X is not a nitrogen atom.

在更佳的實施方案中，

為

、

或

，其中環A’及環B’各自獨立地選自飽和或部分不飽和的3-10員雜環及5-14員雜芳環，該雜環中至多2個環成員為C(=O)，條件是當環B’為含有氮原子的雜環時，該環B’不通過該氮原子與X連接。In a better implementation,

for

,

or

, Wherein ring A'and ring B'are each independently selected from a saturated or partially unsaturated 3-10 membered heterocyclic ring and a 5-14 membered heteroaromatic ring, in which at most 2 ring members are C(=O) , Provided that when the ring B'is a heterocyclic ring containing a nitrogen atom, the ring B'is not connected to X through the nitrogen atom.

在一些實施方案中，

較佳為

；

較佳為

。In some embodiments,

Preferably

；

Preferably

.

在較佳的實施方案中，R⁹ 及R¹⁰ 在每次出現時各自獨立地選自鹵素(例如F、Cl或Br)、甲基、乙基、丙基(例如正丙基或異丙基)、乙烯基、環丙基、環丁基、環戊基、氧雜環丁烷基、單氟甲基、二氟甲基、三氟甲基、-CH₂ CHF₂ 、乙醯基、-OCH₃ 、-CH₂ OH、-CH₂ OCH₃ 、 -CH₂ CH₂ OCH₃ 、-CH₂ -O(P=O)(OH)₂ 、

、

、

、

及 -CH₂ CH₂ -N(CH₃ )₂ 。In a preferred embodiment, each occurrence of R ⁹ and R ¹⁰ is independently selected from halogen (such as F, Cl or Br), methyl, ethyl, propyl (such as n-propyl or isopropyl). ), vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CH ₂ CHF ₂ , acetyl,- OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ -O(P=O)(OH) ₂ ,

,

And -CH ₂ CH ₂ -N(CH ₃ ) ₂ .

在最佳的實施方案中，

選自

、

、

、

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、

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、

、

、

及

，以上基團通過#或##標記的兩個位置之一與X連接，並且另一位置與R¹ 連接，條件是與X連接的原子不是氮原子。In the best implementation,

Selected from

,

and

, The above group is connected to X through one of the two positions marked with # or ##, and the other position is connected to R ¹ , provided that the atom connected to X is not a nitrogen atom.

在較佳的實施方案中，

為

或

，更佳為

或

，其更佳為

、

、

或

，以上基團通過*或**標記的兩個位置之一與Y連接，並且另一位置與X連接，其中---- 表示單鍵或雙鍵且相鄰的鍵不同時為雙鍵； V¹ 、V² 、V³ 、V⁴ 、V⁵ 、V⁶ 、V⁷ 、V⁸ 及V⁹ 在每次出現時各自獨立地選自C、CR⁷ 、C(R⁷ )₂ 、CR⁸ 、C(R⁸ )₂ 、C(=O)、N、NR⁷ 、NR⁸ 、O及S；較佳地，V¹ 、V² 、V³ 、V⁴ 、V⁵ 、V⁶ 、V⁷ 、V⁸ 及V⁹ 在每次出現時各自獨立地選自C、CH、CF、CCl、CCN、CCH₃ 、C-OCH₃ 、CCF₃ 、C-CH₂ -Ph、C-NH-Ph、C-O-Ph、C-CH₂ OCH₃ 、C-CH₂ -NHCH₃ 、C-N(CH₃ )₂ 、C-CH₂ NH₂ 、C-C(=O)OH、C-C(=O)OCH₂ CH₃ 、C-C(=O)NH₂ 、-C-O-CH₂ CH₂ -N(CH₃ )₂ 、CH₂ 、C(=O)、N、NH、NCH₃ 、N-C(=O)CH₃ 、N-Ph、-N-CH₂ CH₂ -N(CH₃ )₂ 、O及S； k為0、1、2、3或4；並且條件是V¹ -V⁹ 中的至多兩個基團同時為C(=O)。In a preferred embodiment,

for

or

, Better

or

, Which is better

,

or

, The above group is connected to Y through one of the two positions marked with * or **, and the other position is connected to X, among them---- Indicates single or double bonds and adjacent bonds are not double bonds at the same time; V¹ , V² , V³ , V⁴ , V⁵ , V⁶ , V⁷ , V⁸ And V⁹ Each occurrence is independently selected from C, CR⁷ , C(R⁷ )₂ , CR⁸ , C(R⁸ )₂ , C(=O), N, NR⁷ , NR⁸ , O and S; preferably, V¹ , V² , V³ , V⁴ , V⁵ , V⁶ , V⁷ , V⁸ And V⁹ Each occurrence is independently selected from C, CH, CF, CCl, CCN, CCH₃ , C-OCH₃ , CCF₃ , C-CH₂ -Ph, C-NH-Ph, C-O-Ph, C-CH₂ OCH₃ , C-CH₂ -NHCH₃ , C-N(CH₃ )₂ , C-CH₂ NH₂ , C-C(=O)OH, C-C(=O)OCH₂ CH₃ , C-C(=O)NH₂ , -C-O-CH₂ CH₂ -N(CH₃ )₂ , CH₂ , C(=O), N, NH, NCH₃ , N-C(=O)CH₃ , N-Ph, -N-CH₂ CH₂ -N(CH₃ )₂ , O and S; k is 0, 1, 2, 3 or 4; and The condition is V¹ -V⁹ At most two groups in are C(=O) at the same time.

在較佳的實施方案中，

為

或

；更佳為

或

。In a preferred embodiment,

for

or

; Better

or

.

在較佳的實施方案中，R⁷ 及R⁸ 在每次出現時各自獨立地選自F、Cl、Br、I、氰基、-N(CH₃ )₂ 、甲基、乙基、丙基、甲氧基、三氟甲基、苯基、-CH₂ -Ph、-NH-Ph、-O-Ph、-CH₂ OCH₃ 、-CH₂ NH₂ 、-CH₂ -NHCH₃ 、-C(=O)CH₃ 、-C(=O)OH、-C(=O)OCH₂ CH₃ 、-C(=O)NH₂ 、-O-CH₂ CH₂ -N(CH₃ )₂ 及-CH₂ CH₂ -N(CH₃ )₂ 。In a preferred embodiment, each occurrence of R ⁷ and R ⁸ is independently selected from F, Cl, Br, I, cyano, -N(CH ₃ ) ₂ , methyl, ethyl, propyl , Methoxy, Trifluoromethyl, Phenyl, -CH ₂ -Ph, -NH-Ph, -O-Ph, -CH ₂ OCH ₃ , -CH ₂ NH ₂ , -CH ₂ -NHCH ₃ , -C (=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₂ CH ₃ , -C(=O)NH ₂ , -O-CH ₂ CH ₂ -N(CH ₃ ) ₂ and -CH ₂ CH ₂ -N(CH ₃ ) ₂ .

在最佳的實施方案中，

為

、

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、

或

，以上基團通過*或**標記的兩個位置之一與Y連接，並且另一位置與X連接。In the best implementation,

for

,

or

, The above group is connected to Y through one of the two positions marked with * or **, and the other position is connected to X.

在較佳的實施方案中，環E為

、

、

或

，較佳為

、

、

或

。In a preferred embodiment, ring E is

,

or

, Preferably

,

or

.

在一些實施方案中，R³ 及R⁴ 在每次出現時各自獨立地選自H、F、Cl、Br、I、-OH、甲基、乙基、丙基、甲氧基、-NH₂ 、 -N(CH₃ )₂ 、-O-亞乙基-N(CH₃ )₂ 。In some embodiments, each occurrence of R ³ and R ⁴ is independently selected from H, F, Cl, Br, I, -OH, methyl, ethyl, propyl, methoxy, -NH ₂ , -N(CH ₃ ) ₂ , -O-ethylene-N(CH ₃ ) ₂ .

在較佳實施方案中，環E為

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。In a preferred embodiment, ring E is

,

or

.

在較佳的實施方案中，R¹ 為甲基、-CH₂ OH、

、

、

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、

、 -C(=O)CF₃ 、-C(=O)CH₂ CF₃ 、-C(=O)CH₂ CN、-C(=O)OCH₃ 、 -C(=O)OC(CH₃ )₃ 、

、

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、

、-S(=O)₂ CH₂ CH₃ 、

、

、-C(=O)CH₂ N(CH₃ )₂ 、

、

、

或

(例如

或

)，更佳為

、

、

、

、

、

、

、

、

或

，其中R¹¹ 為H、鹵素、胺基、氰基、硝基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-C(=O)R⁵ 、-OC(=O)R⁵ 、 -C(=O)OR⁵ 、-OR⁵ 、-SR⁵ 、-S(=O)R⁵ 、-S(=O)₂ R⁵ 、-S(=O)₂ NR⁵ R⁶ 、 -NR⁵ R⁶ 、-C(=O)NR⁵ R⁶ 、-NR⁵ -C(=O)R⁶ 、-NR⁵ -C(=O)OR⁶ 、-NR⁵ -S(=O)₂ -R⁶ 、-NR⁵ -C(=O)-NR⁵ R⁶ 、-C_1-6 亞烷基-NR⁵ R⁶ 或-O-C_1-6 亞烷基 -NR⁵ R⁶ 。In a preferred embodiment, R ¹ is methyl, -CH ₂ OH,

,

, -C(=O)CF ₃ , -C(=O)CH ₂ CF ₃ , -C(=O)CH ₂ CN, -C(=O)OCH ₃ , -C(=O)OC(CH ₃ ) ₃ ,

,

, -S(=O) ₂ CH ₂ CH ₃ ,

,

, -C(=O)CH ₂ N(CH ₃ ) ₂ ,

,

or

(E.g

or

), better

,

or

, Where R ¹¹ is H, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 members Heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O )OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ ,- C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ or -OC _1-6 alkylene-NR ⁵ R ⁶ .

在較佳的實施方案中，R^1a 及R^1b 各自獨立地選自H、甲基、-CF₃ 、乙基、-CH₂ CF₃ 、-CH₂ CH₂ CF₃ 、-CH(CH₃ )CF₃ 、正丙基、異丙基、環丙基、環丁基、環戊基、環己基、-亞乙基-O-甲基、-CH₂ CN、 -CH₂ CH₂ CN、-CH₂ CH₂ OH、

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及

；或者R^1a 及R^1b 連同其所連接的原子共同構成以下基團：

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、

(例如

或

)、

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或

。In a preferred embodiment, R ^1a and R ^1b are each independently selected from H, methyl, -CF ₃ , ethyl, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH(CH ₃ ) CF ₃ , n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ethylene-O-methyl, -CH ₂ CN, -CH ₂ CH ₂ CN, -CH ₂ CH ₂ OH,

,

and

; Or R ^1a and R ^1b together with the atoms to which they are connected form the following groups:

,

(E.g

or

),

,

or

.

在較佳的實施方案中，所述化合物具有任意下式的結構：

、

、 (II) (II’)

、

、 (III) (III’)

、

、 (IV) (IV’)

、

、 (V) (V’)

、

、 (VI) (VI’)

、

、 (VII) (VII’)

、

、 (VIII) (VIII’)

、

、 (IX) (IX’)

、

、 (X) (X’)

、

、 (XI) (XI’)

、

、 (XII) (XII’)

、

、 (XIII) (XIII’)

、

、 (XIV) (XIV’)

、

、 (XV) (XV’)

、

、 (XV)-1 (XV’)-2

、

、 (XV)-3 (XV’)-4

、

； (XVI) (XVI’) 其中： Z選自O、S(=O)_i 及NR；其餘各基團如上文所定義。In a preferred embodiment, the compound has a structure of any of the following formulas:

,

, (II) (II')

,

, (III) (III')

,

, (IV) (IV')

,

, (V) (V')

,

, (VI) (VI')

,

, (VII) (VII')

,

, (VIII) (VIII')

,

, (IX) (IX')

,

, (X) (X')

,

, (XI) (XI')

,

, (XII) (XII')

,

, (XIII) (XIII')

,

, (XIV) (XIV')

,

, (XV) (XV')

,

, (XV)-1 (XV')-2

,

, (XV)-3 (XV')-4

,

; (XVI) (XVI') where: Z is selected from O, S(=O) _i and NR; and the remaining groups are as defined above.

在較佳的實施方案中，所述化合物具有式(XVII)或式(XVII’)的結構：

或

(XVII) (XVII’) 其中： R選自H及C_1-6 烷基；環D為飽和或部分不飽和的3-10員雜環、C_6-10 芳基或5-10員雜芳環，較佳為

、

、

、

、苯環、N-甲基吡咯環、呋喃環或噻吩環； R² 選自H及C_1-6 烷基； R³ 、R⁴ 、R⁷ 、R^7’ 及R⁸ 在每次出現時各自獨立地選自H、鹵素、 -NH₂ 、-OH、C_1-6 烷基及-OR⁵ ； R⁹ 及R¹⁰ 在每次出現時各自獨立地選自H、鹵素、C_1-6 烷基、C_2-6 烯基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-C(=O)R⁵ 及-C_1-6 亞烷基-O(P=O)(OH)₂ ；上述烷基、烯基、環烴基、雜環基、芳基、雜芳基、雜芳環及芳烷基在每次出現時各自視情況經一個或多個獨立地選自鹵素、C_1-6 烷基及 -OR⁵ 的取代基取代； R⁵ 及R⁶ 在每次出現時各自獨立地選自H、C_1-6 烷基、C_3-10 環烴基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基及C_6-12 芳烷基； m在每次出現時各自獨立地為0、1、2或3的整數； n為0、1或2的整數。In a preferred embodiment, the compound has a structure of formula (XVII) or formula (XVII'):

or

(XVII) (XVII') wherein: R is selected from H and C _1-6 alkyl; ring D is a saturated or partially unsaturated 3-10 membered heterocyclic ring, C _6-10 aryl group or 5-10 membered heteroaryl Ring, preferably

,

, Benzene ring, N-methylpyrrole ring, furan ring or thiophene ring; R ^{2 is} selected from H and C _1-6 alkyl; R ³ , R ⁴ , R ⁷ , R ^7'and R ⁸ are each occurrence Each is independently selected from H, halogen, -NH ₂ , -OH, C _1-6 alkyl and -OR ⁵ ; R ⁹ and R ¹⁰ are each independently selected from H, halogen, C _1-6 at each occurrence Alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C (=O)R ⁵ and -C _1-6 alkylene-O(P=O)(OH) ₂ ; the above-mentioned alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, heteroaryl Each occurrence of ring and aralkyl is optionally substituted with one or more substituents independently selected from halogen, C _1-6 alkyl and -OR ⁵ ; R ⁵ and R ⁶ are each substituted for each occurrence Independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl ; M is each independently an integer of 0, 1, 2 or 3 at each occurrence; n is an integer of 0, 1, or 2.

在較佳的實施方案中，R⁵ 及R⁶ 在每次出現時各自獨立地選自H、甲基及乙基。In a preferred embodiment, each occurrence of R ⁵ and R ⁶ is independently selected from H, methyl, and ethyl.

在較佳的實施方案中，R³ 、R⁴ 、R⁷ 、R^7’ 及R⁸ 在每次出現時各自獨立地選自H、F、Cl、Br、-NH₂ 、-OH、甲基、三氟甲基、-CH₂ -Ph、甲氧基、乙氧基及-CH₂ OCH₃ 。In a preferred embodiment, R ³ , R ⁴ , R ⁷ , R ^7'and R ⁸ are each independently selected from H, F, Cl, Br, -NH ₂ , -OH, methyl , Trifluoromethyl, -CH ₂ -Ph, methoxy, ethoxy and -CH ₂ OCH ₃ .

在較佳的實施方案中，R⁹ 及R¹⁰ 在每次出現時各自獨立地選自H、F、Cl、Br、甲基、乙基、正丙基、異丙基、乙烯基、環丙基、環丁基、環戊基、氧雜環丁烷基、單氟甲基、二氟甲基、三氟甲基、乙醯基、-CH₂ CHF₂ 、-CH₂ OH、-CH₂ OCH₃ 、-CH₂ CH₂ OCH₃ 、-CH₂ -O(P=O)(OH)₂ 、

、

及

。In a preferred embodiment, each occurrence of R ⁹ and R ¹⁰ is independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, vinyl, cyclopropyl Group, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, acetyl, -CH ₂ CHF ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ -O(P=O)(OH) ₂ ,

,

and

.

本發明涵蓋對各個實施方案進行任意組合所得的實施方案。The present invention covers embodiments obtained by arbitrarily combining the respective embodiments.

在較佳的實施方案中，所述化合物具有以下結構：編號 結構式 1.

2.

3.

4.

5.

6.

7.

8.

9.

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518.

519.

520.

521.

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530.

531.

532.

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541.

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614.

615.

616.

617.

618.

619.

620.

621.

622.

623.

624.

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626.

627.

628.

629.

630.

631.

632.

633.

634.

635.

636.

637.

638.

639.

640.

641.

642.

643.

644.

645.

646.

647.

648.

649.

650.

651.

652.

653.

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655.

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661.

662.

663.

664.

665.

666.

667.

668.

669.

670.

671.

672.

673.

674.

675.

676.

677.

678.

679.

680.

681.

682.

683.

684.

In a preferred embodiment, the compound has the following structure:

Numbering Structural formula 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

twenty one.

twenty two.

twenty three.

twenty four.

25.

26.

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30.

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33.

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40.

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42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

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174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

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188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267.

268.

269.

270.

271.

272.

273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

334.

335.

336.

337.

338.

339.

340.

341.

342.

343.

344.

345.

346.

347.

348.

349.

350.

351.

352.

353.

354.

355.

356.

357.

358.

359.

360.

361.

362.

363.

364.

365.

366.

367.

368.

369.

370.

371.

372.

373.

374.

375.

376.

377.

378.

379.

380.

381.

382.

383.

384.

385.

386.

387.

388.

389.

390.

391.

392.

393.

394.

395.

396.

397.

398.

399.

400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

430.

431.

432.

433.

434.

435.

436.

437.

438.

439.

440.

441.

442.

443.

444.

445.

446.

447.

448.

449.

450.

451.

452.

453.

454.

455.

456.

457.

458.

459.

460.

461.

462.

463.

464.

465.

466.

467.

468.

469.

470.

471.

472.

473.

474.

475.

476.

477.

478.

479.

480.

481.

482.

483.

484.

485.

486.

487.

488.

489.

490.

491.

492.

493.

494.

495.

496.

497.

498.

499.

500.

501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

513.

514.

515.

516.

517.

518.

519.

520.

521.

522.

523.

524.

525.

526.

527.

528.

529.

530.

531.

532.

533.

534.

535.

536.

537.

538.

539.

540.

541.

542.

543.

544.

545.

546.

547.

548.

549.

550.

551.

552.

553.

554.

555.

556.

557.

558.

559.

560.

561.

562.

563.

564.

565.

566.

567.

568.

569.

570.

571.

572.

573.

574.

575.

576.

577.

578.

579.

580.

581.

582.

583.

584.

585.

586.

587.

588.

589.

590.

591.

592.

593.

594.

595.

596.

597.

598.

599.

600.

601.

602.

603.

604.

605.

606.

607.

608.

609.

610.

611.

612.

613.

614.

615.

616.

617.

618.

619.

620.

621.

622.

623.

624.

625.

626.

627.

628.

629.

630.

631.

632.

633.

634.

635.

636.

637.

638.

639.

640.

641.

642.

643.

644.

645.

646.

647.

648.

649.

650.

651.

652.

653.

654.

655.

656.

657.

658.

659.

660.

661.

662.

663.

664.

665.

666.

667.

668.

669.

670.

671.

672.

673.

674.

675.

676.

677.

678.

679.

680.

681.

682.

683.

684.

在一些實施方案中，所述化合物根據WO 2019/001572 A1 (將其通過援引加入本文)中公開的方法製備。In some embodiments, the compound is prepared according to the method disclosed in WO 2019/001572 A1 (which is incorporated herein by reference).

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥以約0.005 mg/日至約5000 mg/日的量，例如約0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000 mg/日的量給藥。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are in an amount of about 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg/day .

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥以每日約1 ng/kg至約200 mg/kg、約1 μg/kg至約100 mg/kg或者約1 mg/kg至約50 mg/kg體重的量給藥，例如以每單位劑量約1 μg/kg、約10 μg/kg、約25 μg/kg、約50 μg/kg、約75 μg/kg、約100 μg/kg、約125 μg/kg、約150 μg/kg、約175 μg/kg、約200 μg/kg、約225 μg/kg、約250 μg/kg、約275 μg/kg、約300 μg/kg、約325 μg/kg、約350 μg/kg、約375 μg/kg、約400 μg/kg、約425 μg/kg、約450 μg/kg、約475 μg/kg、約500 μg/kg、約525 μg/kg、約550 μg/kg、約575 μg/kg、約600 μg/kg、約625 μg/kg、約650 μg/kg、約675 μg/kg、約700 μg/kg、約725 μg/kg、約750 μg/kg、約775 μg/kg、約800 μg/kg、約825 μg/kg、約850 μg/kg、約875 μg/kg、約900 μg/kg、約925 μg/kg、約950 μg/kg、約975 μg/kg、約1 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約60 mg/kg、約70 mg/kg、約80 mg/kg、約90 mg/kg、約100 mg/kg、約125 mg/kg、約150 mg/kg、約175 mg/kg、約200 mg/kg或約300 mg/kg體重的量給藥。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, The metabolite or prodrug is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg body weight per day, for example At a unit dose of about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/ kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, About 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/ kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, About 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/ kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or about 300 mg/kg body weight.

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥的每日劑量一次性給予或分兩次、三次或四次給予。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, The daily dose of metabolites or prodrugs is given at one time or in two, three or four doses.

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥連續給藥至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 Days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, At least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥給藥一個或多個(例如1、2、3、4、5、6、7、8、9或10個)療程，其中每個療程持續至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；並且每兩個療程之間間隔0、1、2、3、4、5、6、7、8、9、10天、兩周、三周或四周。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, One or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of metabolites or prodrugs, wherein each course lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days , At least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and the interval between every two courses of treatment is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks.

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥通過注射(如靜脈內、動脈內、皮下、腹膜內、肌內注射，包括滴注)或經皮給藥；或通過口服、含服、經鼻、透黏膜、局部、以眼用製劑的形式或通過吸入給藥。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are administered by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip) or transdermal; or by oral, buccal, transnasal, transmucosal, topical, or It can be administered in the form of ophthalmic preparations or by inhalation.

在一些實施方案中，將所述式(I)的化合物或其藥學上可接受的鹽、酯、立體異構體、多晶型物、溶劑合物、N-氧化物、同位素標記的化合物、代謝物或前藥以選自片劑、膠囊劑、錠劑、硬糖劑、散劑、噴霧劑、乳膏劑、軟膏劑、栓劑、凝膠劑、糊劑、洗劑、軟膏劑、水性混懸劑、可注射溶液劑、酏劑及糖漿劑的劑型給藥。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites or prodrugs are selected from tablets, capsules, lozenges, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions In the form of drugs, injectable solutions, elixirs and syrups.

在一些實施方案中，所述預防或治療包括使脂肪變性減少、膠原堆積減少及/或氣球樣變減少。In some embodiments, the prevention or treatment includes reducing steatosis, reducing collagen accumulation, and/or reducing ballooning.

在一些實施方案中，所述方法還包括給藥一種或多種其它的治療劑。In some embodiments, the method further comprises administering one or more other therapeutic agents.

實施例 為了使本發明的目的及技術方案更加清楚，以下結合具體實施例進一步闡述本發明。應理解，這些實施例僅用於說明本發明而不用於限制本發明的範圍。並且，下列實施例中未提及的具體實驗方法，均按照常規實驗方法進行。 Examples In order to make the objectives and technical solutions of the present invention clearer, the present invention will be further described below in conjunction with specific examples. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, the specific experimental methods not mentioned in the following examples are all carried out in accordance with conventional experimental methods.

實施例中所使用化合物C即為化合物331，其根據WO 2019/001572 A1中公開的方法製備。The compound C used in the examples is compound 331, which is prepared according to the method disclosed in WO 2019/001572 A1.

實施例 1 化合物 C 在高脂肪 + 鏈脲佐菌素誘導的小鼠模型中的治療作用 自上海靈暢實驗動物有限公司購買孕鼠。挑選30隻出生2天的雄性新生小鼠用於實驗，每隻小鼠注射200 µg的鏈脲佐菌素(STZ，購於Sigma公司)，從4周齡起通過餵食高脂肪食物2周誘導脂肪性肝炎模型。同時，另選10隻小鼠在不注射STZ的情況下採取正常飲食餵養，作為正常組。高脂飲食2周後，根據小鼠體重情況及空腹血糖水準將小鼠分為3組：模型組、化合物C給藥組及替米沙坦給藥組(替米沙坦購於TOKYO CHEMICAL)，並開始給藥，每天1次經口給藥，連續給藥21天，記錄動物分組見表1。每天記錄小鼠體重(見圖1A及圖1B)，並在最後一次給藥後記錄小鼠禁食後體重(見表2以及圖2A及圖2B)。對動物處以安樂死，取肝臟組織稱重並進行氣球樣變、脂肪變性以及膠原堆積等組織學評分(盲評)。組織學改變通過對肝臟組織H&E染色、油紅O染色、天狼星紅染色進行評價，其中H&E染色用於評價肝細胞氣球樣變，油紅O用於反映肝脂肪變性，天狼星紅染色用於評價膠原堆積，相關評分見圖3A、圖3B及圖3C，對各項組織學改變抑制率見表3。 Example 1 Therapeutic effect of compound C in a mouse model induced by high fat + streptozotocin . Pregnant mice were purchased from Shanghai Lingchang Experimental Animal Co., Ltd. Thirty two-day-old male newborn mice were selected for the experiment. Each mouse was injected with 200 µg of streptozotocin (STZ, purchased from Sigma), and induced by feeding high-fat food for 2 weeks from the age of 4 weeks. Steatohepatitis model. At the same time, another 10 mice were selected and fed with a normal diet without STZ injection as the normal group. After 2 weeks of high-fat diet, the mice were divided into 3 groups according to their body weight and fasting blood glucose level: model group, compound C administration group and telmisartan administration group (telmisartan purchased from TOKYO CHEMICAL) , And started the administration, once a day orally for 21 consecutive days. The recorded animal groups are shown in Table 1. The weight of the mice was recorded every day (see Figure 1A and Figure 1B), and the weight of the mice after fasting was recorded after the last administration (see Table 2 and Figure 2A and Figure 2B). The animals were euthanized, and the liver tissues were weighed and histological scores (blind evaluation) such as ballooning, steatosis, and collagen accumulation were performed. The histological changes were evaluated by H&E staining, oil red O staining, and Sirius red staining of liver tissue. H&E staining was used to evaluate hepatocyte ballooning, oil red O was used to reflect liver steatosis, and Sirius red staining was used to evaluate collagen. The related scores are shown in Figure 3A, Figure 3B and Figure 3C, and the inhibition rate of various histological changes is shown in Table 3.

評分原則：脂肪變性評分為0-3分，病變面積＜5%評為0分，病變面積為5-33%評為1分，病變面積為33-66%評為2分，病變面積＞66%評為3分；肝細胞氣球樣變評分為0-2分，無氣球樣變評為0分，少量氣球樣變評為1分，多數細胞或明顯氣球樣變評為2分；膠原堆積評分為0-4分，評分原則參考Brunt EM, et al. Hepatology. 2011中報導的原則。Scoring principle: steatosis score is 0-3 points, lesion area is less than 5% as 0 points, lesion area is 5-33% as 1 point, lesion area is 33-66% as 2 points, and lesion area>66 % Is rated as 3 points; hepatocyte ballooning score is 0-2 points, no ballooning is rated as 0 points, a small amount of ballooning is rated as 1 point, most cells or obvious ballooning is rated as 2 points; collagen accumulation The score is 0-4 points, and the scoring principle refers to the principle reported in Brunt EM, et al. Hepatology. 2011.

表3中的脂肪變性、肝細胞氣球樣變以及肝組織膠原堆積的抑制率(%)分別通過以下公式計算(正常組評分為0)：In Table 3, the inhibition rate (%) of steatosis, hepatocyte ballooning and liver tissue collagen accumulation are calculated by the following formula (the normal group score is 0):

對脂肪變性損傷的抑制率(%)=100%×(模型組平均評分-給藥組平均評分)/(模型組平均評分-正常組評分)Inhibition rate of steatosis injury (%) = 100% × (average score of model group-average score of administration group) / (average score of model group-score of normal group)

對肝細胞氣球樣變損傷的抑制率(%)=100%×(模型組平均評分-給藥組平均評分)/(模型組平均評分-正常組評分)Inhibition rate of hepatocyte ballooning injury (%) = 100% × (average score of model group-average score of administration group) / (average score of model group-score of normal group)

對肝組織膠原堆積的抑制率(%)=100%×(模型組平均評分-給藥組平均評分)/(模型組平均評分-正常組評分)Inhibition rate of collagen accumulation in liver tissue (%) = 100% × (average score of model group-average score of administration group) / (average score of model group-score of normal group)

表 1 實驗動物分組分組 動物數 ( 隻 ) 給藥劑量 (mg/kg 體重 ) 給藥體積 (ml/kg 體重 ) 給藥途徑 給藥頻率 正常組 10 無* 5 經口給藥每天1次，連續21天模型組 10 無* 5 經口給藥每天1次，連續21天化合物C給藥組 10 100 5 經口給藥每天1次，連續21天替米沙坦給藥組 10 50 5 經口給藥每天1次，連續21天 * 向正常組及模型組的動物給溶媒(由PEG400、Tween-80及水組成)。 Table 1 Group of experimental animals Grouping Number of animals ( only ) Dosage (mg/kg body weight ) Dosing volume (ml/kg body weight ) Route of administration Dosing frequency normal group 10 no* 5 Oral administration 1 time a day for 21 consecutive days Model group 10 no* 5 Oral administration 1 time a day for 21 consecutive days Compound C administration group 10 100 5 Oral administration 1 time a day for 21 consecutive days Telmisartan administration group 10 50 5 Oral administration 1 time a day for 21 consecutive days *The vehicle (consisting of PEG400, Tween-80 and water) was given to animals in the normal group and the model group.

表 2 實驗終點動物體重變化與肝臟重量變化分組體重 (g) 肝臟重量 (mg) 肝重 / 體重 (%) 正常組 20.3±0.33 805.8±25.27 4.0±0.11 模型組 16.0±0.27 862.4±13.46 5.4±0.13 化合物C給藥組 17.1±0.59 872.3±17.91 5.1±0.15 替米沙坦給藥組 15.7±0.84 760.1±48.78 4.9±0.39 Table 2 Changes in animal body weight and liver weight at the end of the experiment Grouping Weight (g) Liver weight (mg) Liver weight / body weight (%) normal group 20.3±0.33 805.8±25.27 4.0±0.11 Model group 16.0±0.27 862.4±13.46 5.4±0.13 Compound C administration group 17.1±0.59 872.3±17.91 5.1±0.15 Telmisartan administration group 15.7±0.84 760.1±48.78 4.9±0.39

表 3 化合物C對脂肪變性、肝細胞氣球樣變、膠原堆積的抑制率分組 對脂肪變性損傷的抑制率 (%) 對肝細胞氣球樣變損傷的抑制率 (%) 對肝組織膠原堆積的抑制率 (%) 化合物C給藥組 66.67 60.00 44.44 替米沙坦給藥組 -11.17 11.12 38.27 Table 3 Inhibition rate of compound C on steatosis, hepatocyte ballooning and collagen accumulation Grouping Inhibition rate of steatosis injury (%) Inhibition rate of hepatocyte ballooning injury (%) Inhibition rate of collagen accumulation in liver tissue (%) Compound C administration group 66.67 60.00 44.44 Telmisartan administration group -11.17 11.12 38.27

由實驗結果可見，化合物C在STZ聯合高脂誘導的小鼠模型中表現出良好的耐受性及明顯的治療效果，化合物C主要通過改善肝組織脂肪變性、氣球樣變及膠原堆積三個方面發揮治療作用。From the experimental results, it can be seen that compound C shows good tolerance and obvious therapeutic effect in the mouse model induced by STZ combined with high fat. Compound C mainly improves liver fatty degeneration, ballooning and collagen accumulation in three aspects. Play a therapeutic role.

實施例 2 化合物 C 在高脂肪 + 高膽固醇 + 高糖 + 四氯化碳誘導的小鼠模型中的治療作用 將8-10周齡小鼠(購自江蘇集萃藥康生物科技有限公司)通過給予西方飲食(高脂肪+高膽固醇飼料，購自北京華阜康生物科技股份有限公司)及高糖溶液(23.1 g/L D-果糖及18.9 g/L D-葡萄糖)飼養聯合腹腔注射四氯化碳誘導脂肪性肝炎模型。自西方飲食+高糖溶液飼養開始後第7天(D7)腹腔注射0.05 ml的20%四氯化碳，每週一次，給予12次。在第28天對動物進行分組(每組8隻動物)：模型組(給予溶媒，由PEG400、吐溫-80及去離子水組成)、化合物C給藥組(100 mg/kg)及替米沙坦給藥組(10 mg/kg)。溶媒、化合物C、替米沙坦均經口給藥，第28天開始給藥，每天1次，21天為1個療程，治療3個療程，每個療程間隔1周。同時，設置正常對照組，該組中小鼠以正常飼料及正常飲水飼養。最後一次給藥後2h對動物進行外周血採血並分離血清，並對動物執行安樂死，取肝組織。血清主要用於檢測膽固醇及低密度脂蛋白含量。肝組織用天狼星紅染色以評價膠原堆積，並且通過流式細胞技術檢測內皮細胞及巨噬細胞比例以反映肝損傷。 Example 2 The therapeutic effect of compound C in a mouse model induced by high fat + high cholesterol + high sugar + carbon tetrachloride. 8-10 week old mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were administered by Western diet (high fat + high cholesterol feed, purchased from Beijing Huafukang Biotechnology Co., Ltd.) and high sugar solution (23.1 g/L D-fructose and 18.9 g/L D-glucose) feeding combined with intraperitoneal injection of tetrachloride Carbon-induced steatohepatitis model. On the 7th day (D7) after the western diet + high-sugar solution feeding started, 0.05 ml of 20% carbon tetrachloride was intraperitoneally injected, once a week, 12 times. On the 28th day, the animals were divided into groups (8 animals in each group): model group (administered with vehicle, consisting of PEG400, Tween-80 and deionized water), compound C administration group (100 mg/kg) and tilmi Sartan administration group (10 mg/kg). The vehicle, compound C, and telmisartan were all administered orally, starting on the 28th day, once a day, 21 days as a course of treatment, and 3 courses of treatment, with an interval of 1 week between each course. At the same time, a normal control group was set up, in which mice were fed with normal feed and normal drinking water. Two hours after the last administration, the animals were subjected to peripheral blood sampling and serum separation. The animals were euthanized and liver tissues were taken. Serum is mainly used to detect cholesterol and low-density lipoprotein content. Liver tissue was stained with Sirius Red to evaluate collagen accumulation, and the ratio of endothelial cells and macrophages was detected by flow cytometry to reflect liver damage.

如圖4A及圖4B所示，與正常對照組相比，模型組小鼠膠原堆積明顯增加。與模型組相比，化合物C給藥組(p＜0.01)及替米沙坦給藥組(p＜0.01)顯著下調肝組織中的膠原堆積。As shown in Figure 4A and Figure 4B, compared with the normal control group, collagen accumulation in the model group increased significantly. Compared with the model group, the compound C administration group (p<0.01) and the telmisartan administration group (p<0.01) significantly down-regulated collagen accumulation in liver tissue.

如圖5A及圖5B所示，與正常對照組相比，模型組小鼠血清膽固醇(p＜0.01)及低密度脂蛋白(p＜0.001)水準顯著升高。與模型組相比，化合物C給藥組顯著下調血清膽固醇(p＜0.05)及低密度脂蛋白(p＜0.05)水準。替米沙坦對二者沒有影響。As shown in Figure 5A and Figure 5B, compared with the normal control group, the serum cholesterol (p<0.01) and low-density lipoprotein (p<0.001) levels of the model group mice were significantly increased. Compared with the model group, the compound C administration group significantly down-regulated serum cholesterol (p<0.05) and low-density lipoprotein (p<0.05) levels. Telmisartan has no effect on both.

如圖6A及圖6B所示，與正常對照組相比，模型組小鼠肝組織內皮細胞減少，而巨噬細胞水準增加。與模型組相比，化合物C增加了小鼠肝組織內皮細胞(p＜0.01)比例，同時也一定程度降低了巨噬細胞所占比例。與替米沙坦給藥組相比，化合物C對內皮細胞作用強於替米沙坦，對巨噬細胞下調作用二者相當。As shown in Figure 6A and Figure 6B, compared with the normal control group, the mouse liver tissue endothelial cells in the model group decreased, while the macrophage level increased. Compared with the model group, compound C increased the proportion of mouse liver tissue endothelial cells (p<0.01), and also reduced the proportion of macrophages to a certain extent. Compared with the telmisartan administration group, compound C had stronger effects on endothelial cells than telmisartan, and the downregulation effects on macrophages were similar.

實施例 3 化合物 C 在高脂肪 + 高膽固醇 + 四氯化碳誘導的小鼠模型中的治療作用 將8-10周齡小鼠(購自江蘇集萃藥康生物科技有限公司)通過給予西方飲食(高脂肪+高膽固醇飼料，購自北京華阜康生物科技股份有限公司)飼養聯合腹腔注射四氯化碳誘導脂肪性肝炎模型。實驗動物根據體重隨機分為3組(每組8隻動物)：模型組(給予溶媒，由PEG400、吐溫-80及去離子水組成)、化合物C-給藥組(100 mg/kg)及替米沙坦給藥組(10 mg/kg)。各組自西方飲食飼養開始後第5天(D5)腹腔注射0.05 ml的20% CCl₄ ，每週一次，給予12次。在第21天開始給藥或溶媒。溶媒、化合物C、替米沙坦均經口給藥，每天1次，21天為1個療程，治療3個療程，每個療程間隔1周。同時，設置正常對照組，該組中小鼠以正常飼料及正常飲水飼養。最後一次給藥後2h對動物進行外周血採血並分離血清，並對動物執行安樂死，取肝組織。血清主要用於檢測膽固醇及低密度脂蛋白含量。肝組織用於天狼星紅染色以評價膠原堆積。 Example 3 Therapeutic effect of compound C in a mouse model induced by high fat + high cholesterol + carbon tetrachloride. 8-10 week old mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were given a western diet ( High-fat + high-cholesterol feed, purchased from Beijing Huafukang Biotechnology Co., Ltd.) was fed to a model of steatohepatitis induced by intraperitoneal injection of carbon tetrachloride. The experimental animals were randomly divided into 3 groups (8 animals in each group) according to their body weight: the model group (given the vehicle, consisting of PEG400, Tween-80 and deionized water), the compound C-administration group (100 mg/kg) and Telmisartan administration group (10 mg/kg). Each group was intraperitoneally injected with 0.05 ml of 20% CCl _{4 on} the 5th day (D5) after the start of Western diet feeding, once a week, 12 times. Start administration or vehicle on day 21. The vehicle, compound C, and telmisartan were all administered orally, once a day, 21 days as a course of treatment, and 3 courses of treatment, with an interval of 1 week between each course. At the same time, a normal control group was set up, in which mice were fed with normal feed and normal drinking water. Two hours after the last administration, the animals were subjected to peripheral blood sampling and serum separation. The animals were euthanized and liver tissues were taken. Serum is mainly used to detect cholesterol and low-density lipoprotein content. Liver tissue was stained with Sirius Red to evaluate collagen accumulation.

如圖7A及圖7B所示，在西方飲食+四氯化碳誘導的小鼠脂肪性肝炎模型中，與正常對照組相比，模型組小鼠膠原堆積明顯增加。與模型組相比，化合物C給藥組(p＜0.01)顯著下調肝組織中的膠原堆積。替米沙坦給藥組對膠原堆積沒有抑制作用，與模型組相比無顯著性差異(p＞0.05)。As shown in Figure 7A and Figure 7B, in the mouse steatohepatitis model induced by Western diet + carbon tetrachloride, collagen accumulation in the model group increased significantly compared with the normal control group. Compared with the model group, the compound C administration group (p<0.01) significantly down-regulated collagen accumulation in liver tissue. Telmisartan administration group has no inhibitory effect on collagen accumulation, and there is no significant difference compared with model group (p>0.05).

如圖8A及圖8B所示，與正常對照組相比，模型組小鼠血清膽固醇(p＜0.001)及低密度脂蛋白(p＜0.001)水準顯著升高。與模型組相比，化合物C給藥組顯著下調血清膽固醇(p＜0.01)及低密度脂蛋白(p＜0.01)水準。替米沙坦對二者沒有影響。As shown in Figure 8A and Figure 8B, compared with the normal control group, the serum cholesterol (p<0.001) and low-density lipoprotein (p<0.001) levels of the model group increased significantly. Compared with the model group, the compound C administration group significantly reduced serum cholesterol (p<0.01) and low-density lipoprotein (p<0.01) levels. Telmisartan has no effect on both.

實施例 4 化合物 C 在四氯化碳誘導的小鼠模型中的治療作用 將8-10周齡小鼠(購自江蘇集萃藥康生物科技有限公司)通過體重隨機分為4組(每組8隻動物)：模型組(給予溶媒，0.5% CMC-Na)、化合物C-300 mg/kg給藥組、化合物C-100 mg/kg給藥組、替米沙坦給藥組(10 mg/kg)，並開始腹腔注射0.05 ml的40% CCl₄ ，每週2次，連續6周。第15天開始灌胃給藥，每天一次，連續28天。同時，設置正常對照組，該組中小鼠以正常飼料及正常飲水飼養。最後一次給藥後2h對動物執行安樂死，取肝組織進行天狼星紅染色，評價膠原堆積。 Example 4 Therapeutic effect of compound C in a mouse model induced by carbon tetrachloride. 8-10 week old mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were randomly divided into 4 groups (each group 8 Animals): model group (vehicle, 0.5% CMC-Na), compound C-300 mg/kg administration group, compound C-100 mg/kg administration group, telmisartan administration group (10 mg/kg) kg), and started intraperitoneal injection of 0.05 ml of 40% CCl ₄ twice a week for 6 consecutive weeks. Gavage was started on the 15th day, once a day for 28 consecutive days. At the same time, a normal control group was set up, in which mice were fed with normal feed and normal drinking water. The animals were euthanized 2 hours after the last administration, and liver tissues were taken for Sirius red staining to evaluate collagen accumulation.

如圖9A及圖9B所示，在四氯化碳誘導的小鼠模型中，與正常對照組相比，模型組小鼠膠原堆積明顯增加。與模型組相比，化合物C-300 mg/kg給藥組(p＜0.001)及100 mg/kg給藥組(p＜0.001)均顯著下調膠原在肝組織堆積，高劑量組作用優於低劑量組。替米沙坦給藥組對膠原堆積沒有抑制作用，與模型組相比無顯著性差異(p＞0.05)。As shown in Figure 9A and Figure 9B, in the carbon tetrachloride-induced mouse model, collagen accumulation in the model group increased significantly compared with the normal control group. Compared with the model group, the compound C-300 mg/kg administration group (p＜0.001) and the 100 mg/kg administration group (p＜0.001) significantly down-regulated collagen accumulation in liver tissue, and the high-dose group had better effects than low Dose group. Telmisartan administration group has no inhibitory effect on collagen accumulation, and there is no significant difference compared with model group (p>0.05).

實施例 5 化合物 C 對高脂肪 + 高膽固醇飲食聯合 N- 二乙基亞硝胺誘導的大鼠模型的治療作用 自上海吉輝公司購入SD大鼠孕鼠，將由其獲得的新生大鼠用於本研究。挑選40隻雄性新生大鼠，於出生2周後單次注射N-二乙基亞硝胺(DEN，購於Sigma公司)。將新生大鼠繼續用母鼠乳汁飼養2周後，根據動物體重隨機分為4組(每組10隻)：模型組(0.5% CMC-Na)、化合物C-50 mg/kg給藥組、化合物C-100 mg/kg給藥組、奧貝膽酸(OCA，購自武漢藥明康得合成，30 mg/kg)給藥組，並採取西方飲食(高脂肪+高膽固醇飼料，購於南通特羅菲飼料科技有限公司，蘇飼證(2014)06092)飲食飼養8周。同時，另選8隻雄性新生大鼠，出生後母乳餵養4周，然後採用正常飼料替代高脂肪+高膽固醇飲食進行飼養，作為正常對照組。溶媒(0.5% CMC-Na)、化合物C、OCA均採取灌胃方式給藥，每天一次，於高脂肪+高膽固醇飲食飼養開始後第8天開始給藥，連續給藥49天。給藥方案見表4。 Example 5 Therapeutic effect of compound C on a rat model induced by high-fat + high-cholesterol diet combined with N -diethylnitrosamine. SD rat pregnant rats were purchased from Shanghai Jihui Company, and the newborn rats obtained therefrom were used in this study the study. Forty male newborn rats were selected and injected with N-diethylnitrosamine (DEN, purchased from Sigma) 2 weeks after birth. After feeding the newborn rats with mother mouse milk for 2 weeks, they were randomly divided into 4 groups (10 in each group) according to the animal weight: model group (0.5% CMC-Na), compound C-50 mg/kg administration group, Compound C-100 mg/kg administration group, obeticholic acid (OCA, purchased from Wuhan WuXi Kangde Synthetic, 30 mg/kg) administration group, and a Western diet (high fat + high cholesterol feed, purchased from Nantong) Trofe Feed Technology Co., Ltd., Su Shizhen (2014) 06092) was fed diet for 8 weeks. At the same time, another 8 male newborn rats were selected, breast-fed for 4 weeks after birth, and then fed with normal feed instead of a high-fat + high-cholesterol diet as a normal control group. The vehicle (0.5% CMC-Na), compound C, and OCA were administered by gavage, once a day, on the 8th day after the start of the high-fat + high-cholesterol diet, for 49 consecutive days. The dosage regimen is shown in Table 4.

於最後一次給藥2h後對動物執行安樂死，取肝組織，肝組織經固定包埋後，用H&E染色(染色圖像參見圖10A)進行NAS評分。相關評分標準見表5。The animals were euthanized 2 hours after the last administration, liver tissue was taken, and the liver tissue was fixed and embedded, and stained with H&E (see Figure 10A for stained images) for NAS score. The relevant scoring criteria are shown in Table 5.

表table 44 給藥方案Dosing regimen 組別Group 動物數(隻)Number of animals (only) 是否給與高脂肪+高膽固醇飲食Whether to give a high fat + high cholesterol diet 給藥Administration 給藥途徑Route of administration 給藥時間Administration time 組1Group 1 88 否no 溶媒(0.5% CMC-Na)Solvent (0.5% CMC-Na) 經口給藥Oral administration 每天1次，連續49天Once a day for 49 consecutive days 組2Group 2 1010 是Yes 溶媒(0.5% CMC-Na)Solvent (0.5% CMC-Na) 經口給藥Oral administration 每天1次，連續49天Once a day for 49 consecutive days 組3Group 3 1010 是Yes OCA-30 mg/kgOCA-30 mg/kg 經口給藥Oral administration 每天1次，連續49天Once a day for 49 consecutive days 組4Group 4 1010 是Yes 化合物C-50 mg/kgCompound C-50 mg/kg 經口給藥Oral administration 每天1次，連續49天Once a day for 49 consecutive days 組5Group 5 1010 是Yes 化合物C-100 mg/kgCompound C-100 mg/kg 經口給藥Oral administration 每天1次，連續49天Once a day for 49 consecutive days

表table 5 NAS5 NAS 評分標準Grading 病理表現Pathological manifestations 評分標準Grading 評分原則Scoring principle 肝細胞氣球樣變Hepatocyte ballooning 無no 00 少量細胞氣球樣變A small amount of cell ballooning 11 大量細胞氣球樣變Massive cell ballooning 22 小葉炎症：炎性細胞浸潤灶Lobular inflammation: inflammatory cell infiltration foci 無no 00 200×視野觀察出現＜2個炎性細胞浸潤灶Observed by 200× visual field, there are less than 2 inflammatory cell infiltration foci 11 200×視野觀察出現2-4個炎性細胞浸潤灶200× visual field observation showed 2-4 inflammatory cell infiltration foci 22 200×視野觀察出現＞4個炎性細胞浸潤灶Observed by 200× visual field, there are more than 4 inflammatory cell infiltration foci 33 肝細胞脂肪變性：占整個切片面積比例Fatty degeneration of hepatocytes: the proportion of the whole slice area ＜5%＜5% 00 5%-33%5%-33% 11 ＞33%-66%＞33%-66% 22 ＞66%＞66% 33

NAS評分是肝脂肪變性評分、炎性細胞浸潤評分及肝細胞氣球樣變評分的總和。模型組的NAS評分較正常組明顯增加，達到6分，化合物C治療組動物肝組織NAS評分顯著降低至大約4.2 (參見圖10B)The NAS score is the sum of the liver steatosis score, inflammatory cell infiltration score, and hepatocyte ballooning score. Compared with the normal group, the NAS score of the model group was significantly increased to 6 points, and the liver tissue NAS score of the animal in the compound C treatment group was significantly reduced to about 4.2 (see Figure 10B)

除本文中描述的那些外，根據前述描述，本發明的各種修改對本發明所屬技術領域中具有通常知識者而言會是顯而易見的。這樣的修改也意圖落入所附申請專利範圍內。本申請中所引用的各參考文獻(包括所有專利、專利申請、期刊文章、書籍及任何其它公開)均以其整體援引加入本文。In addition to those described herein, various modifications of the present invention will be apparent to those having ordinary knowledge in the technical field to which the present invention belongs based on the foregoing description. Such modifications are also intended to fall within the scope of the attached patent application. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

圖1顯示實驗期間動物的體重(圖1A)及體重變化(圖1B)。圖2顯示給藥結束時各組動物的平均體重(圖2A)及肝重/體重百分比(圖2B)。圖3顯示給藥結束後肝組織的脂肪變性損傷抑制率(圖3A)、膠原堆積抑制率(圖3B)以及氣球樣變抑制率(圖3C)。圖4A顯示實施例2中肝組織天狼星紅染色(100×)圖像，其中A為正常組，B為模型組，C為化合物C-100 mg/kg給藥組，D為替米沙坦給藥組。圖4B顯示實施例2中肝組織的膠原堆積。圖5A顯示實施例2的小鼠模型中的血清膽固醇水準。圖5B顯示實施例2的小鼠模型中的血清低密度脂蛋白水準。圖6A顯示實施例2的肝組織中的內皮細胞百分比。圖6B顯示實施例2的肝組織中的巨噬細胞百分比。圖7A顯示實施例3中肝組織天狼星紅染色(200×)圖像，其中A為正常組，B為模型組，C為化合物C-100 mg/kg給藥組，D為替米沙坦給藥組。圖7B顯示實施例3中肝組織的膠原堆積。圖8A顯示實施例3的小鼠模型中的血清膽固醇水準。圖8B顯示實施例3的小鼠模型中的血清低密度脂蛋白水準。圖9A顯示實施例4中肝組織天狼星紅染色(100×)圖像，其中A為正常組，B為模型組，C為化合物C-300 mg/kg給藥組，D為化合物C-100 mg/kg給藥組，E為替米沙坦給藥組。圖9B顯示實施例4中肝組織的膠原堆積。圖10A顯示實施例5中肝組織H&E染色圖像，A為正常對照組，其中肝組織結構完整，細胞排列規則；B為模型組，其中肝組織具有明顯肝細胞脂肪變性，呈透明空泡樣，有氣球樣變及炎性細胞浸潤灶；C為OCA-30 mg/kg給藥組；D為化合物C-50 mg/kg給藥組；E為化合物C-100 mg/kg給藥組。圖10B顯示實施例5中肝組織的NAS評分。Figure 1 shows the animal's body weight (Figure 1A) and weight change (Figure 1B) during the experiment. Figure 2 shows the average body weight of each group of animals at the end of the administration (Figure 2A) and liver weight/body weight percentage (Figure 2B). Figure 3 shows the inhibition rate of fatty degeneration injury of the liver tissue (Figure 3A), the inhibition rate of collagen accumulation (Figure 3B), and the inhibition rate of ballooning (Figure 3C) after the administration. Figure 4A shows the Sirius Red staining (100×) image of liver tissue in Example 2, where A is the normal group, B is the model group, C is the compound C-100 mg/kg administration group, and D is the telmisartan administration group. FIG. 4B shows the collagen accumulation of liver tissue in Example 2. FIG. Figure 5A shows serum cholesterol levels in the mouse model of Example 2. Figure 5B shows the serum low-density lipoprotein level in the mouse model of Example 2. Figure 6A shows the percentage of endothelial cells in the liver tissue of Example 2. Figure 6B shows the percentage of macrophages in the liver tissue of Example 2. Figure 7A shows the image of Sirius red staining (200×) of liver tissue in Example 3, where A is the normal group, B is the model group, C is the compound C-100 mg/kg administration group, and D is the telmisartan administration group. FIG. 7B shows the collagen accumulation of liver tissue in Example 3. FIG. Figure 8A shows the serum cholesterol level in the mouse model of Example 3. Figure 8B shows the serum low-density lipoprotein level in the mouse model of Example 3. Figure 9A shows the Sirius Red staining (100×) image of liver tissue in Example 4, where A is the normal group, B is the model group, C is the compound C-300 mg/kg administration group, and D is the compound C-100 mg /kg administration group, E is the telmisartan administration group. FIG. 9B shows the collagen accumulation of liver tissue in Example 4. FIG. Figure 10A shows the H&E stained image of the liver tissue in Example 5. A is the normal control group, in which the liver tissue structure is complete and the cells are arranged regularly; B is the model group, in which the liver tissue has obvious fatty degeneration of hepatocytes, showing clear vacuoles , There are ballooning and inflammatory cell infiltration foci; C is the OCA-30 mg/kg administration group; D is the compound C-50 mg/kg administration group; E is the compound C-100 mg/kg administration group. FIG. 10B shows the NAS score of liver tissue in Example 5. FIG.

Claims

Use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, It is used to prepare medicines for the prevention, alleviation and/or treatment of fatty liver disease and/or steatohepatitis, wherein the compound of formula (I) is:

,

and

, Acetyl,

,

,

,

,

,

,

,

,

and

When, ring C is not a 5-membered heteroaromatic ring; and when one of R ¹ and R ¹⁰ is H and the other is H or acetyl, ring D does not exist; R ^1a and R ^1b are each independently selected from H, Halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _{6- 10} aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O) -NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-OR ⁵ and -OC _1-6 alkylene-NR ⁵ R ⁶ , provided that R ^When one of ^1a and R ^1b is n-propyl, the other is not H; or R ^1a and R ^1b together with the atoms to which they are connected form a 3-12 member heterocyclic or heteroaromatic ring; R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from H, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O )R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ ,- S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 Alkylene-O(P=O)(OH) ₂ and -OC _1-6 Alkylene-NR ⁵ R ⁶ ; The above-mentioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, hetero Cyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic and aralkyl groups are each substituted with one or more substituents independently selected from the following when each occurrence: halogen, hydroxy, Oxo, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3- 10-membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O) R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S (=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 Alkyl -NR ⁵ R ⁶ , the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group are further optionally substituted with one or more substituents independently selected from the following: halogen, hydroxy , Oxo, amino, cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl; R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _{6- 10} aryl groups, 5-14 membered heteroaryl groups and C _6-12 aralkyl groups; m is each independently an integer of 0, 1, 2 or 3 at each occurrence; n is an integer of 0, 1 or 2; i is an integer of 0, 1 or 2; and g is an integer of 0, 1, 2, 3 or 4; wherein the fatty liver disease is preferably alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD ), the steatohepatitis is preferably alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH).

Such as the use of claim 1, wherein the compound has any structure of the following formula:

,

, (II) (II')

,

, (III) (III')

,

, (IV) (IV')

,

, (V) (V')

,

, (VI) (VI')

,

, (VII) (VII')

,

, (VIII) (VIII')

,

, (IX) (IX')

,

, (X) (X')

,

, (XI) (XI')

,

, (XII) (XII')

,

, (XIII) (XIII')

,

, (XIV) (XIV')

,

, (XV) (XV')

,

, (XV)-1 (XV')-2

,

, (XV)-3 (XV')-4

,

, (XVI) (XVI')

or

(XVII) (XVII') where: Z is selected from O, S(=O) _i and NR; R ¹¹ is H, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C (=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(= O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene -NR ⁵ R ⁶ or -OC _1-6 alkylene-NR ⁵ R ⁶ ; the remaining groups are as defined in claim 1.

Such as the use of claim 1, wherein the compound has the following structure: Numbering Structural formula 1.

2.

3.

4.

5.

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.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation In an amount of about 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150 , 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 Administered in mg/day.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation At about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg per day of a substance, isotope-labeled compound, metabolite or prodrug The amount of body weight is administered, for example, per unit dose of about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg /kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg , About 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg /kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg , About 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg /kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or about 300 mg/kg body weight.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation The daily doses of substances, isotope-labeled compounds, metabolites or prodrugs are given at one time or in two, three or four doses.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation For at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, or at least 11 days for continuous administration of substances, isotopically-labeled compounds, metabolites or prodrugs , At least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation One or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of drug, isotope-labeled compound, metabolite or prodrug, wherein each course lasts at least 3 Days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, At least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 Days, at least 45 days, or at least 50 days; and there is an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks between every two treatment courses.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation Drugs, isotope-labeled compounds, metabolites or prodrugs are administered by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip) or transdermally; or by oral, buccal, or nasal , Transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

The use according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidation Substance, isotope-labeled compound, metabolite or prodrug selected from tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion , Ointments, aqueous suspensions, injectable solutions, elixirs and syrups.

As for the use of any one of claims 1 to 3, the prevention or treatment includes reducing steatosis, reducing collagen accumulation and/or reducing ballooning.

Such as the use of any one of claims 1 to 3, which also includes the administration of one or more other therapeutic agents.